Journal articles: 'Childhood onset; Autosomal recessive; Neurones'

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Ebrahimi-Fakhari, Darius. "Congenital Disorders of Autophagy: What a Pediatric Neurologist Should Know." Neuropediatrics 49, no. 01 (November 7, 2017): 018–25. http://dx.doi.org/10.1055/s-0037-1608652.

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AbstractAutophagy is a fundamental and conserved intracellular pathway that mediates the degradation of macromolecules and organelles in lysosomes. Proper autophagy function is important for central nervous system development and neuronal function. Over the last 5 years, several single gene disorders of the autophagy pathway have emerged: EPG5-associated Vici syndrome, WDR45-associated β-propeller protein-associated neurodegeneration, SNX14-associated autosomal-recessive spinocerebellar ataxia 20, ATG5-associated autosomal-recessive ataxia syndrome, SQSTM1/p62-associated childhood-onset neurodegeneration, and several forms of the hereditary spastic paraplegias. This novel and evolving group of disorders is characterized by prominent central nervous system involvement leading to brain malformations, developmental delay, intellectual disability, epilepsy, movement disorders, and neurodegeneration. Predominant involvement of the long white matter tracts and the cerebellum are anatomic and imaging hallmarks, with common findings that include a thinning of the corpus callosum and cerebellar hypoplasia or atrophy. A storage disease phenotype by clinical or imaging criteria is present in some diseases. Most congenital disorders of autophagy are progressive and over time involve pathology in multiple brain regions. This review provides a detailed clinical, imaging and genetic characterization of congenital disorders of autophagy and highlights the importance of this pathway for childhood-onset neurological diseases.

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Borman, Arundhati Dev. "Childhood-Onset Autosomal Recessive Bestrophinopathy." Archives of Ophthalmology 129, no. 8 (August 1, 2011): 1088. http://dx.doi.org/10.1001/archophthalmol.2011.197.

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Patel, Shailendra B., and Srujana Kamala Yada. "Adult Onset Isolated Hypogonadotropic Hypogonadism- a Cause of Secondary Amenorrhea." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A777. http://dx.doi.org/10.1210/jendso/bvab048.1581.

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Abstract A 23-year-old African American female was referred for secondary amenorrhea evaluation. She attained menarche at 12 years and had regular menses. At 18 years, she used OCPs for few months, and used plan B, after which her menses stopped. She had hot flashes and sweating. She was placed on progesterone, but never had withdrawal bleeding. Review of systems was positive for intentional weight loss after her menses stopped, hair loss and nipple discharge. She denied any loss of sensation of smell. She has a PMH of asthma, anxiety and OSA. Family history was not significant for any fertility issues. She smoked cannabis after menses stopped. On physical examination, vitals were stable, BMI of 35 kg/meter2, well-developed secondary sexual characteristics, no thyromegaly, acne or hirsutism. Upon work up, CBC, CMP were normal, Urine pregnancy test was negative, gonadotropins were undetectable (FSH- <0.7mIU/ml, LH- <0.2mIU/ml), anti-mullerian hormone was 3.82ng/ml (WNL), Estradiol was also absent (<15pg/ml), with a low Total testosterone (11ng/dl), TSH was 1.17uIU/ml, Free T4 was 1.1ng/dl, ACTH was 9.58pg/ml, Cortisol was 14.8mcg/dl, and Prolactin was 1.5ng/ml. MRI brain was normal with normal pituitary gland, no focal lesion visualized. Pelvic ultrasound showed ovaries 5.9mL and 4.6mL with multiple follicles present bilaterally. Diagnosis of adult-onset isolated hypogonadotropic hypogonadism (IHH) was made. Patient was started on estradiol patches and progesterone. IHH is a genetic disorder of defective production or action of GnRH. IHH when associated with anosmia is called Kallmann syndrome. It was first described by German American geneticist Joseph Kallmann in 1944. GnRH is a decapeptide, produced in arcuate nucleus and pre-optic nucleus of hypothalamus. GnRH stimulates anterior pituitary to secrete FSH and LH. IHH is caused due to impaired migration of GnRH neurons to brain during embryogenesis. It is inherited as autosomal or X-linked dominant or recessive. Gene mutations associated are ANOS-1, FGFR, PROK-2. It is rare in females. IHH has a broad spectrum of clinical presentation from complete absence of sexual development to partial completion of puberty. It presents with microphallus, cryptorchidism, cleft lip/palate, syndactyly, renal aplasia. In childhood presents with anosmia, hearing deficits, dental agenesis, mirror movements, short stature. During puberty, absent pubertal growth spurt, amenorrhea, lack of virilization, no secondary sexual characteristics, infertility. In partial forms, known as Adult onset or acquired form of IHH, patients have slight testicular growth, thelarche, menarche. Goals of treatment are- pubertal induction, maintenance of sexual maturation and restoration of fertility. In females, pre-puberty only estrogen is given, after puberty both estrogen and progesterone are used, for fertility, pulsatile gonadotropins or GnRH analogues are used.

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Brahe, C., S. Zappata, G. Neri, S. Servidei, E. Ricci, and P. Tonali. "Genetic homogeneity between childhood-onset and adult-onset autosomal recessive spinal muscular atrophy." Lancet 346, no. 8977 (September 1995): 741–42. http://dx.doi.org/10.1016/s0140-6736(95)91507-9.

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Gu, Su-min, Debra A. Thompson, C. R. Srisailapathy Srikumari, Birgit Lorenz, Ulrich Finckh, Aileen Nicoletti, K. R. Murthy, et al. "Mutations in RPE65 cause autosomal recessive childhood–onset severe retinal dystrophy." Nature Genetics 17, no. 2 (October 1997): 194–97. http://dx.doi.org/10.1038/ng1097-194.

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Mutlu-Albayrak, Hatice, Emre Kırat, and Gürkan Gürbüz. "Childhood-onset autosomal recessive ataxias: a cross-sectional study from Turkey." neurogenetics 21, no. 1 (November 19, 2019): 59–66. http://dx.doi.org/10.1007/s10048-019-00597-y.

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Shenoy, Rathika D., Deepthi R. V., Nutan Kamath, and Sumana J. Kamath. "DEVELOPMENTAL DELAY IN CHILDHOOD CATARACT: A CAVEAT MARINESCO-SJÖGREN SYNDROME." Journal of Health and Allied Sciences NU 04, no. 03 (September 2014): 121–23. http://dx.doi.org/10.1055/s-0040-1703818.

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AbstractWe report on a child with Marinesco-Sjögren Syndrome, a rare autosomal recessive disorder characterised by early onset cataract, psychomotor delay, cerebellar hypoplasia and myopathy. The presentation, neuro-imaging and muscle biopsy features are discussed.

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Руденская, Г. Е., В. А. Кадникова, А. Л. Чухрова, Т. В. Маркова, and О. П. Рыжкова. "Rare autosomal recessive spastic paraplegias." Nauchno-prakticheskii zhurnal «Medicinskaia genetika», no. 11() (November 29, 2019): 26–35. http://dx.doi.org/10.25557/2073-7998.2019.11.26-35.

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Актуальность. Наследственные спастические параплегии (НСП) - одна из наиболее гетерогенных групп наследственных нервных болезней, насчитывающая около 80 клинико-генетических форм (SPG) с хронологической нумерацией. Методы высокопроизводительного экзомного секвенирования (MPS) принципиально расширили возможности выделения новых SPG и практической ДНК-диагностики. В ФГБНУ МГНЦ проводится первое в России комплексное клинико-молекулярное исследование НСП на основе MPS и ряда дополнительных методов ДНК-анализа. Группа верифицированных случаев насчитывает 114 семей с 20 различными формами, включая редкие аутосомно-рецессивные (АР) формы, мало известные генетикам и неврологам. Цель: представить первые российские наблюдения редких АР форм: SPG5, SPG26, SPG35 и SPG39, связанных соответственно с генами CYP7B1, B4GALNT1, FA2H и PNPLA6, участвующими в разных звеньях липидного обмена. Методы. Первичная группа включала около 200 российских семей с предварительным клиническим диагнозом НСП или сходных болезней; основная группа: 114 семей с диагностированной формой SPG; материал статьи: 4 семьи. Использованы методы: клинико-генеалогический, кастомная MPS-панель «параплегии» (64 гена); секвенирование по Сэнгеру; мультиплексная-лигаза зависимая амплификация MLPA (выборочно); полноэкзомное секвенирование WES (выборочно); биоинформатический анализ. Результаты: подгруппа АР SPG включила 22 семьи/12 форм. Представленные 4 формы выявлены в единичных семьях. SPG5: подросток 17 лет в русской семье; начало в 15 лет, умеренный спастический парапарез, легкая сопутствующая атаксия. Генотип CYP7B1: ранее описанные мутации с.334С>T (p.Arg112Ter)/c.1190C>T (p.Pro397Leu) у больного и здоровой сестры 8 лет (доклиническая стадия), родители - гетерозиготные носители. SPG26: мальчик 13 лет в неинбредной русской семье; начало в раннем детстве, медленно прогрессирующий спастический парапарез, дизартрия, когнитивные и поведенческие нарушения, нормальная МРТ. Генотип B4GALNT1: новая мутация c.1514G>C (p.Arg505Pro) в гомозиготном состоянии у больного, в гетерозиготном - у родителей. Случай SPG26 - 14-й описанный в мире, гомозиготность по мутации, вызывающей очень редкую форму SPG, в неинбредной русской семье необычна. SPG35: мальчик 5 лет в этнически смешанной семье (мать русская, отец татарско-бурятского происхождения) из Сибири; начало в 4 года, быстро прогрессирующий спастический парапарез без других симптомов, нормальная МРТ. Генотип FA2H: ранее описанная мутация с.805С>T (p.Arg269Cys) и новая мутация c.106C>T (p.Leu36Phe). SPG39: мальчик 10 лет в русско-татарской семье; начало в 5 лет, умеренный спастический парапарез без других симптомов. Генотип PNPLA6: описанная ранее интронная мутация с.199-2A>T / новая мутация c.2033G>A (p.Gly678Asp), родители - гетерозиготные носители. Выводы. НСП у российских больных представлены широким спектром клинико-генетических форм, включая редкие АР SPG в неинбредных русских и в этнически смешанных семьях. Cлучаи SPG5, SPG26, SPG35 и SPG39 - первые российские описания. Из найденных в 4 генах 7 мутаций три ранее не описаны. MPS - метод выбора ДНК-диагностики болезней с выраженной генетической гетерогенностью, таких, как НСП. Objective: hereditary spastic paraplegias (HSP) are a heterogeneous group including about 80 forms: SPGs (Spastic Paraplegia Gene) numbered chronologically. Massive parallel sequencing MPS greatly improved possibilities of new SPGs disclosure and of practical DNA diagnostics. First Russian HSP complex investigation of HSP using MPS is being performed in FSBI PCMG. By now, the group of genetically diagnosed cases numbers 114 families with 20 different SPGs, including rare autosomal recessive forms poorly known to geneticists and neurologists. Aim: to present first Russian cases of rare autosomal recessive (AR) forms: SPG5, SPG26, SPG35, and SPG39. The genes, CYP7B1, B4GALNT1, FA2H, and FA2H correspondingly, are involved in lipid metabolism. Materials: initial group: about 200 Russian families with preliminary clinical diagnosis of HSP or alike disorders; index group: 114 SPG-confirmed families; paper material: the four families. Methods: clinical investigation, genealogical analysis; molecular methods: custom MPS-panel “paraplegias” (63 genes), Sanger sequencing, multiplex ligation-dependent probe amplification MLPA (selectively), whole-exome sequencing WES (selectively); bioinformatic analysis. Results. Subgroup of AR SPG included 22 families/12 forms. SPG5, 26, 35, 39 were detected in single families. SPG5: a 17-year-old youth in a Russian family; onset in 15 years, moderate spastic paraparesis, mild ataxia; CYP7B1 genotype: two earlier reported mutations .334С>T (p.Arg112Ter) и c.1190C>T (p.Pro397Leu) in the patient and in unaffected younger sister (preclinical stage), parents - heterozygous carries. SPG26: a 13-year old boy in a Russian non-consanguineous family; early-childhood onset, slowly progressing paraparesis, dysarthria, cognitive and behavioral impairment; B4GALNT1 genotype: novel homozygous mutation c.1514G>C (p.Arg505Pro) in the boy, heterozygosity in parents; homozygosity for a very rare gene (14th SPG26 world case) in a Russian non-consanguineous family is unusual. SPG35: a 5-year-old boy in a Sibirian ethnically mixed family (Russian mother, father of Tatar-Buryat ethnicity); onset in 4 years, rapidly progressing paraparesis with no other signs, normal MRI; FA2H genotype: reported earlier с.805С>T (p.Arg269Cys) / novel c.106C>T (p.Leu36Phe). SPG39: a 10-year-old boy in a Russian-Tatar family; onset in 5 years, slowly progressing paraparesis with no other signs; PNPLA6 genotype: reported earlier intronic с.199-2A>T novel c.2033G>A (p.Gly678Asp), parents - heterozygous carriers. Conclusions. HSP in Russian patients present a wide spectrum including rare AR SPG in non-consanguineous Russian families and in families of mixed ethnicity. Our SPG5, SPG26, SPG35 and SPG39 cases are first in Russia; of 7 mutations detected in the 4 genes 3 mutations were novel. MPS is method of choice in DNA diagnostics of heterogeneous disorders like HSP.

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Halsey, Christina, Solomon A. Ndoni, Roya Babaei-Jadidi, David Roper, Barbara J. Wild, Tom J. Vulliamy, Paul J. Thornalley, and Mark Layton. "A Novel Therapeutic Approach in Triosephosphate Isomerase Deficiency." Blood 108, no. 11 (November 16, 2006): 3735. http://dx.doi.org/10.1182/blood.v108.11.3735.3735.

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Abstract Triosephosphate isomerase (TPI) deficiency is an autosomal recessive disorder characterised by congenital haemolytic anaemia and progressive neuromuscular dysfunction. No specific treatment exists to alter the natural history and death usually follows in infancy or early childhood. Biochemically TPI deficiency is distinguished by dramatic accumulation of the triose phosphate dihydroxyacetonephosphate (DHAP). DHAP undergoes spontaneous catabolism to methylglyoxal (MG) a potent mediator of protein and nucleotide glycation. MG levels are elevated in TPI deficiency and correlate with neuromuscular dysfunction. Accumulation of triose phosphates may be inhibited through stimulation of the pentose phosphate pathway by maximizing the activity of transketolase which converts glyceraldehyde-3-phosphate into ribose-5-phosphate. Transketolase activity can be enhanced by supplementation with the co-factor thiamine. Thiamine has been shown to reduce triosephosphate accumulation in human red blood cells in vitro but hitherto this not been studied in vivo. We report the outcome of a trial of thiamine supplementation in a female infant born to consanguineous south Asian parents who presented with a haemolytic anaemia at 3 weeks of age followed by neurological symptoms at 11 months culminating in respiratory failure requiring long-term mechanical ventilation. The diagnosis of TPI deficiency was made on the basis of enzyme assay and subsequent genetic analysis which demonstrated homozygosity for the Glu105Asp mutation of the TPI gene previously described in kindreds of European origin. There was marked elevation of red cell DHAP (550 % normal mean). Oral supplementation was commenced at 12 months of age with a lipophilic thiamine derivative - benzoyloxymethylthiamine - chosen to maximize potential CNS bioavailability at a dose of 5mg/kg/day. Response was assessed clinically and by assay of intermediates and metabolites in urine, blood, and CSF on day 0,1,7 and 14. Following thiamine supplementation there was a transient reduction in ventilatory requirement. A maximal (2–3 fold) increase in red cell thiamine and thiamine diphosphate (TPP) concentration was seen at 7 days. Red cell transketolase activity below that of saturation with TPP cofactor was 10% at day 0 and decreased to 0% thereafter. Despite persistently elevated DHAP levels a marked reduction in the MG metabolite D-Lactate of 90% in urine and 57% in the CSF was seen at day 14. Glyoxal a product of lipid peroxidation was also significantly reduced in CSF (70%). After 6 weeks the patient remained dependent on mechanical ventilation and the trial was discontinued. In conclusion oral thiamine supplementation was well tolerated and led to enhanced transketolase activity associated with indicators of reduced MG flux. Intervention preceding the onset of irreversible neuronal damage should be evaluated. Thiamine supplementation holds promise for the prevention and treatment of other neurodegenerative diseases and diabetic complications in which MG-mediated protein glycation is implicated.

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Burguêz, Daniela, Camila Maria de Oliveira, Marcio Aloísio Bezerra Cavalcanti Rockenbach, Helena Fussiger, Leonardo Modesti Vedolin, Pablo Brea Winckler, Marcelo Krieger Maestri, et al. "Autosomal recessive spastic ataxia of Charlevoix-Saguenay: a family report from South Brazil." Arquivos de Neuro-Psiquiatria 75, no. 6 (June 2017): 339–44. http://dx.doi.org/10.1590/0004-282x20170044.

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ABSTRACT Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset, neurodegenerative disorder caused by mutations in SACS, firstly reported in Quebec, Canada. The disorder is typically characterized by childhood onset ataxia, spasticity, neuropathy and retinal hypermyelination. The clinical picture of patients born outside Quebec, however, is often atypical. In the present article, the authors describe clinical and neuroradiological findings that raised the suspicion of an ARSACS diagnosis in two female cousins with Germanic background from Rio Grande do Sul, Brazil. We present a review on the neuroimaging, ophthalmologic and neurophysiologic clues for ARSACS diagnosis. The early-onset, slowly progressive, spastic-ataxia phenotype of reported patients was similar to ARSACS patients from Quebec. The SACS sequencing revealed the novel homozygous c.5150_5151insA frameshift mutation confirming the ARSACS diagnosis. ARSACS is a frequent cause of early onset ataxia/spastic-ataxia worldwide, with unknown frequency in Brazil.

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Patni, Nivedita, Sarah Hatab, Chao Xing, Zhengyang Zhou, Claudia Quittner, and Abhimanyu Garg. "A novel autosomal recessive lipodystrophy syndrome due to homozygous LMNA variant." Journal of Medical Genetics 57, no. 6 (December 19, 2019): 422–26. http://dx.doi.org/10.1136/jmedgenet-2019-106395.

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BackgroundDespite major advances in understanding the molecular basis of various genetic lipodystrophy syndromes, some rare patients still remain unexplained.CasesWe report a novel autosomal recessive lipodystrophy affecting two sisters aged 17 and 19 years and characterised by early onset intellectual disability, and subsequent development of near-generalised loss of subcutaneous fat with diabetes mellitus, extreme hypertriglyceridemia, hepatic steatosis, short stature, clinodactyly, joint contractures, leiomyoma of uterus and cataracts in childhood. The lipodystrophy was more pronounced in the upper and lower extremities, and there was no associated muscular hypertrophy. Using whole exome sequencing in this consanguineous Hispanic pedigree, we report disease-causing homozygous p.Arg545His LMNA variant in the affected subjects, and confirm the lack of pathogenic variants in other known lipodystrophy genes. The mother and a younger brother were both heterozygous for p.Arg545His LMNA variant and were overweight with acanthosis nigricans without any evidence of lipodystrophy. Our patients are distinct from previously reported autosomal recessive lipodystrophy syndromes and have no overlap with other autosomal recessive laminopathies, including mandibuloacral dysplasia, Emery-Dreifuss muscular dystrophy and Charcot-Marie-Tooth neuropathy.ConclusionOur report of this unusual familial generalised lipodystrophy syndrome adds to the pleiotropy associated with biallelic autosomal recessive LMNA variants.

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Barnicoat, A. "Medical genetics: advances in brief: Genetic homogeneity between childhood-onset and adult-onset autosomal recessive spinal muscular atrophy." Journal of Medical Genetics 32, no. 12 (December 1, 1995): 996. http://dx.doi.org/10.1136/jmg.32.12.996-b.

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Kawai, H., M. Akaike, T. Endo, K. Adachi, T. Inui, T. Mitsui, S. Kashiwagi, T. Fujiwara, S. Okuno, and S. Shin. "Adhalin gene mutations in patients with autosomal recessive childhood onset muscular dystrophy with adhalin deficiency." Journal of Clinical Investigation 96, no. 3 (September 1, 1995): 1202–7. http://dx.doi.org/10.1172/jci118152.

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Sansbury, Francis H., Birgül Kirel, Richard Caswell, Hana Lango Allen, Sarah E. Flanagan, Andrew T. Hattersley, Sian Ellard, and Charles J. Shaw-Smith. "Biallelic RFX6 mutations can cause childhood as well as neonatal onset diabetes mellitus." European Journal of Human Genetics 23, no. 12 (August 12, 2015): 1744–48. http://dx.doi.org/10.1038/ejhg.2015.161.

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Abstract Neonatal diabetes is a highly genetically heterogeneous disorder. There are over 20 distinct syndromic and non-syndromic forms, including dominant, recessive and X-linked subtypes. Biallelic truncating or mis-sense mutations in the DNA-binding domain of the RFX6 transcription factor cause an autosomal recessive, syndromic form of neonatal diabetes previously described as Mitchell–Riley syndrome. In all, eight cases have been reported, with the age at onset of diabetes in the first 2 weeks of life. Here we report two individuals born to double first cousins in whom intestinal atresias consistent with a diagnosis of Mitchell–Riley syndrome were diagnosed at birth, but in whom diabetes did not present until the ages of 3 and 6 years. Novel compound heterozygous RFX6 nonsense mutations (p.Arg726X/p.Arg866X) were identified at the 3′ end of the gene. The later onset of diabetes in these patients may be due to incomplete inactivation of RFX6. Genetic testing for RFX6 mutations should be considered in patients presenting with intestinal atresias in the absence of neonatal diabetes.

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Maystadt, I., M. Zarhrate, D. Leclair-Richard, B. Estournet, A. Barois, F. Renault, M. C. Routon, et al. "A gene for an autosomal recessive lower motor neuron disease with childhood onset maps to 1p36." Neurology 67, no. 1 (May 25, 2006): 120–24. http://dx.doi.org/10.1212/01.wnl.0000223834.55225.2d.

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FUCHSHUBER, ARNO, OLIVIER GRIBOUVAL, VERA RONNER, SABINE KROISS, STEPHANIE KARLE, MATTHIAS BRANDIS, and FRIEDHELM HILDEBRANDT. "Clinical and Genetic Evaluation of Familial Steroid-Responsive Nephrotic Syndrome in Childhood." Journal of the American Society of Nephrology 12, no. 2 (February 2001): 374–78. http://dx.doi.org/10.1681/asn.v122374.

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Abstract. Steroid-responsive idiopathic nephrotic syndrome (SSINS) is the most common form of nephrotic syndrome in childhood. This article reports a cohort of familial SSINS with disease onset in childhood. The clinical course in terms of age at onset, symptoms during the initial phase, renal morphology, and outcome was evaluated. Furthermore, linkage toNPHS2, the gene for autosomal-recessive steroid-resistant INS on chromosome 1, was examined. Two families with haplotypes consistent with linkage toNPHS2were evaluated for mutations in theNPHS2gene. Familial SSINS (32 patients from 15 families, minimal change NS in 12 of 12 biopsies) was found to be a clinically homogeneous entity. Interfamilial and intrafamilial variability with respect to the age at disease onset was low, indicating a strong genetic influence on disease onset. By linkage studies and mutational analysis, familial SSINS was found to be genetically distinct fromNPHS2. This is the first report of a large cohort of familial SSINS. Exclusion of linkage toNPHS2makes likely the existence of a distinct gene locus for SSINS.

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Breedveld, G. J. "A new locus for a childhood onset, slowly progressive autosomal recessive spinocerebellar ataxia maps to chromosome 11p15." Journal of Medical Genetics 41, no. 11 (November 1, 2004): 858–66. http://dx.doi.org/10.1136/jmg.2004.019232.

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Gribaa, M., M. Salih, M. Anheim, C. Lagier-Tourenne, D. H'mida, N. Drouot, A. Mohamed, et al. "A new form of childhood onset, autosomal recessive spinocerebellar ataxia and epilepsy is localized at 16q21-q23." Brain 130, no. 7 (May 29, 2007): 1921–28. http://dx.doi.org/10.1093/brain/awm078.

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Lusk, Laina, Emily Black, and Jaime Vengoechea. "Segregation of two variants suggests the presence of autosomal dominant and recessive forms of WFS1-related disease within the same family: expanding the phenotypic spectrum of Wolfram Syndrome." Journal of Medical Genetics 57, no. 2 (July 30, 2019): 121–23. http://dx.doi.org/10.1136/jmedgenet-2018-105782.

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BackgroundWFS1 was initially described as causative agent of autosomal recessive (AR) Wolfram syndrome, a childhood-onset disorder involving diabetes, optic atrophy, hearing loss and neurodegenerative features. However, the discovery of autosomal dominant (AD) disorders caused by this gene has resulted in clinical counselling and result interpretation challenges.ObjectiveWe seek to report a family that appears to segregate dominant and recessive forms of WFS1-related disease.Methods/resultsA 19-year-old woman presented with progressive childhood sensorineural hearing loss and recent optic atrophy, with biallelic mutations in WFS1: c.2486T>C (likely pathogenic) and c.2470G>A (uncertain significance). Her A1C was normal. Her sister carried the same variants and had a similar phenotype. Their father carried c.2486T>C and was found to have mild–moderate hearing loss but no optic atrophy or neurological symptoms. The mother carried c.2470G>A and had a normal audiogram and ophthalmological exam. Providing anticipatory guidance for this family was difficult given the phenotypic variability of WFS1-related disorders and the uncertainty surrounding whether the inheritance pattern was AR or AD.ConclusionThe clinical correlation of the variants identified in this family suggests an AR Wolfram-like syndrome, without the typical diabetes mellitus or diabetes insipidus nor neurological decline. To our knowledge, this is a novel WFS1-related phenotype.

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Scott, Hamish S., Jun Kudoh, Marie Wattenhofer, Kazunori Shibuya, Asher Berry, Roman Chrast, Michel Guipponi, et al. "Insertion of β-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness." Nature Genetics 27, no. 1 (January 2001): 59–63. http://dx.doi.org/10.1038/83768.

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Chen, Dong-Hui, Caitlin Latimer, Mayumi Yagi, Mesaki Kenneth Ndugga-Kabuye, Elyana Heigham, Suman Jayadev, James S. Meabon, et al. "Heterozygous STUB1 missense variants cause ataxia, cognitive decline, and STUB1 mislocalization." Neurology Genetics 6, no. 2 (February 20, 2020): e397. http://dx.doi.org/10.1212/nxg.0000000000000397.

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ObjectiveTo identify the genetic cause of autosomal dominant ataxia complicated by behavioral abnormalities, cognitive decline, and autism in 2 families and to characterize brain neuropathologic signatures of dominant STUB1-related ataxia and investigate the effects of pathogenic variants on STUB1 localization.MethodsClinical and research-based exome sequencing was used to identify the causative variants for autosomal dominant ataxia in 2 families. Gross and microscopic neuropathologic evaluations were performed on the brains of 4 affected individuals in these families.ResultsMutations in STUB1 have been primarily associated with childhood-onset autosomal recessive ataxia, but here we report heterozygous missense variants in STUB1 (p.Ile53Thr and p.The37Leu) confirming the recent reports of autosomal dominant inheritance. Cerebellar atrophy on imaging and cognitive deficits often preceded ataxia. Unique neuropathologic examination of the 4 brains showed the marked loss of Purkinje cells (PCs) without microscopic evidence of significant pathology outside the cerebellum. The normal pattern of polarized somatodendritic STUB1 protein expression in PCs was lost, resulting in aberrant STUB1 localization in the distal PC dendritic arbors.ConclusionsThis study confirms a dominant inheritance pattern in STUB1-ataxia in addition to a recessive one and documents its association with cognitive and behavioral disability, including autism. In the most extensive analysis of cerebellar pathology in this disease, we demonstrate disruption of STUB1 protein in PCs as part of the underlying pathogenesis.

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Lee, Y. J. "Pathogenic mutations but not polymorphisms in congenital and childhood onset autosomal recessive deafness disrupt the proteolytic activity of TMPRSS3." Journal of Medical Genetics 40, no. 8 (August 1, 2003): 629–31. http://dx.doi.org/10.1136/jmg.40.8.629.

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Birla, Shweta, Deepak Khandelwal, Arundhati Sharma, and Rajesh Khadgawat. "MC4R Mutation in Early-onset Severe Childhood Obesity—Genotype–phenotype Correlation." US Endocrinology 13, no. 02 (2017): 69. http://dx.doi.org/10.17925/use.2017.13.02.69.

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Melanocortin-4 receptor (MC4R; OMIM#155541) encodes a 332-amino acids protein possessing typical G-protein-coupled receptors’ (GPCRs) structural design having three intact and functional domains, mutations which lead to the most recurrent type of monogenic obesity. Methods: We report here a case of a 5-year-old boy from Iraq who presented to the clinic for evaluation of progressive weight gain since he was 6 months of age. There were no symptoms of hypothalamic dysfunction except increase in appetite. His height was 120 cm (97th centile of the Centers for Disease Control and Prevention [CDC] growth chart, mid parental height was 50th centile), weight was 57 kg (>97th centile on CDC chart) and body mass index was 39.6 kg/m2 (>97th centile on CDC chart). A monogenic cause of obesity was strongly suspected in view of early onset severe childhood obesity. Results: Mutation screening of MC4R revealed a homozygous isoleucine by arginie at codon 69 (I69R) mutation in the patient, while his father was heterozygous for this mutation. Conclusion: We describe a monogenic form of obesity with characteristic presentation due to I69R MC4R mutation inherited as an autosomal recessive condition. The finding is different from previous reports which have documented this mutation to be inherited in a dominant manner. The findings of the present study reiterate the complex nature of obesity with possible involvement of modifier genes and/or genetic heterogeneity in its causation.

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Peddareddygari, Leema Reddy, Kinsi Oberoi, and Raji P. Grewal. "Clinical and Genetic Analysis of an Asian Indian Family with Charcot-Marie-Tooth Disease Type 4C." Case Reports in Neurology 10, no. 1 (February 9, 2018): 38–44. http://dx.doi.org/10.1159/000486589.

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Charcot-Marie-Tooth disease type 4C, an autosomal recessive genetic neuropathy, is caused by mutations in the SH3TC2 (SH3 domain and tetratricopeptide repeats 2) gene. Interestingly, although mutations in this gene have been observed in European gypsies, a population that originated in India, there are few publications describing Indian patients. We report our analysis of a 50-year-old woman of Asian Indian descent with onset of progressive distal weakness and sensory loss in childhood. A clinical examination revealed the presence of a neuropathy with pes cavus without spinal abnormalities. Electrophysiological testing confirmed a sensorimotor length-dependent neuropathy with demyelinating features. A genetic analysis revealed she carries 2 novel mutations, c.2488G>T variant (rs879254317) and c.731+5G>A variant (rs879254316), in the SH3TC2 gene. Further genetic testing demonstrated that her son is a carrier of the c.731+5G>A mutation. Our analysis confirms that this patient is a compound heterozygote inheriting these mutations, which are in trans, in an autosomal recessive pattern. Her son developed an episode of sciatic neuropathy with complete resolution. We hypothesize that in his case, haploinsufficiency caused by c.731+5G>A mutation may have predisposed him to the development of this focal neuropathy.

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Fagerberg, Christina R., Adrian Taylor, Felix Distelmaier, Henrik D. Schrøder, Maria Kibæk, Dagmar Wieczorek, Mark Tarnopolsky, et al. "Choline transporter-like 1 deficiency causes a new type of childhood-onset neurodegeneration." Brain 143, no. 1 (December 19, 2019): 94–111. http://dx.doi.org/10.1093/brain/awz376.

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Abstract Cerebral choline metabolism is crucial for normal brain function, and its homoeostasis depends on carrier-mediated transport. Here, we report on four individuals from three families with neurodegenerative disease and homozygous frameshift mutations (Asp517Metfs*19, Ser126Metfs*8, and Lys90Metfs*18) in the SLC44A1 gene encoding choline transporter-like protein 1. Clinical features included progressive ataxia, tremor, cognitive decline, dysphagia, optic atrophy, dysarthria, as well as urinary and bowel incontinence. Brain MRI demonstrated cerebellar atrophy and leukoencephalopathy. Moreover, low signal intensity in globus pallidus with hyperintensive streaking and low signal intensity in substantia nigra were seen in two individuals. The Asp517Metfs*19 and Ser126Metfs*8 fibroblasts were structurally and functionally indistinguishable. The most prominent ultrastructural changes of the mutant fibroblasts were reduced presence of free ribosomes, the appearance of elongated endoplasmic reticulum and strikingly increased number of mitochondria and small vesicles. When chronically treated with choline, those characteristics disappeared and mutant ultrastructure resembled healthy control cells. Functional analysis revealed diminished choline transport yet the membrane phosphatidylcholine content remained unchanged. As part of the mechanism to preserve choline and phosphatidylcholine, choline transporter deficiency was implicated in impaired membrane homeostasis of other phospholipids. Choline treatments could restore the membrane lipids, repair cellular organelles and protect mutant cells from acute iron overload. In conclusion, we describe a novel childhood-onset neurometabolic disease caused by choline transporter deficiency with autosomal recessive inheritance.

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Saadi, Nebal Wael. "Early onset familial relapsing polyneuropathy, mimicking CIDP; A lesson from clinical genetics." Journal of the Faculty of Medicine Baghdad 62, no. 4 (February 21, 2021): 128–31. http://dx.doi.org/10.32007/jfacmedbagdad.6241765.

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Background: In children, chronic immune-mediated neuropathies present with slowly progressive or relapsing episodes of gait difficulty, symmetric weakness and sometimes paraesthesia. Infancy and early childhood age of presentation and familial recurrence are believed to be atypical features. Case presentation: Herein, we describe two brothers from a non- consanguineous Iraqi family, who presented with episodes of acute immune-mediated demyelinating peripheral neuropathy in early infancy that relapsed recurrently. Mild haemolytic anaemia was also reported. Inherited metabolic disorders were suspected and Whole Exome Sequencing of the youngest brother revealed homozygous frame shift mutation in CD59 gene, confirming the diagnosis of autosomal recessive hemolytic anemia, CD59-mediated, with or without immune-mediated polyneuropathy (HACD59). Conclusion: The report highlights the advantage of genetic testing in such rare and inherited conditions. In the lack of necessary non-traditional diagnostic methods, it is substantial to maintain the accustomed medical practice and strategies, based on available clinical data.

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Popova, Irina Yu, Tatiana A. Grebennikova, Anatoly N. Tiulpakov, Kristina S. Kulikova, Liudmila Y. Rozhinskaya, and Zhanna E. Belaya. "Rare genetic diseases of the bone tissue: the case of a family with osteogenesis imperfecta and X-linked hypophosphataemia." Osteoporosis and Bone Diseases 21, no. 1 (April 25, 2018): 28–33. http://dx.doi.org/10.14341/osteo9756.

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Osteogenesis imperfecta (OI) and X-linked hypophosphataemia (XLH) are rare genetic diseases, which lead to childhood-onset bone fragility, low-trauma fractures and limb deformities. OI occurs as a result of impaired type 1 collagen synthesis at different stages, depending on the type of a genetic mutation, which leads to bone strength impairment. In most cases OI is a disorder with an autosomal dominant inheritance. However, there are also cases of autosomal recessive inheritance. To date, 16 types of OI are distinguished, with type 2 being the most severe due to 100% mortality rate in neonatal and perinatal periods. XLH is characterized by altered bone mineralization due to impaired phosphorus absorption and reabsorption, as a result of mutations in the PHEX gene. The bone tissue «softens», and this process is accompanied by deformities in long tubular bones. In this article we describe the family, in which both diseases are presented, despite their rarity. The case is investigated from points of view: the clinician’s and the patient’s perspective.

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TSUKAGUCHI, HIROYASU, HENRY YAGER, JOHN DAWBORN, LUIS JOST, JERRY COHLMIA, PATRICIA F. ABREU, APARECIDO B. PEREIRA, and MARTIN R. POLLAK. "A Locus for Adolescent and Adult Onset Familial Focal Segmental Glomerulosclerosis on Chromosome 1q25-31." Journal of the American Society of Nephrology 11, no. 9 (September 2000): 1674–80. http://dx.doi.org/10.1681/asn.v1191674.

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Abstract. Focal segmental glomerulosclerosis is a nonspecific renal lesion observed both as a primary (idiopathic) entity and in a secondary form, typically in association with reduced functional renal mass. Familial forms have been observed and two loci for autosomal dominant FSGS have been mapped. This study shows that an adolescent/adult form of recessive FSGS maps to a locus on chromosome 1q25-31, which overlaps with a region previously identified as harboring a locus for an early childhood onset recessive form of nephrotic syndrome (SRN1). Evaluation of a large family demonstrated linkage with a maximum two-point lod score of 3.98 at D1S254 and D1S222. Lod score calculations support the conclusion of linkage in four of five additional families. Haplotype analysis suggests that this FSGS gene is located in a 19-cM region flanked by D1S416 and D1S413, of which 6 cM overlaps with SRN1, suggesting that these distinct clinical subsets of kidney disease may be allelic. These regions may also overlap with the syntenic region of the glomerulosclerosis susceptibility locus in the BUF/Mna rat. Because the presentation of FSGS may be subtle, inherited FSGS may be much more common than generally realized and grossly underestimated because of the absence of clear familial patterns. This result increases the suspicion that polymorphisms at this locus may contribute to sporadic FSGS.

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Tamhankar, Parag Mohan, Bin Zhu, Vasundhara Parag Tamhankar, Shilpa Mithbawkar, Luis Seabra, John H. Livingston, Takeshi Ikeuchi, and Yanick J. Crow. "A Novel Hypomorphic CSF1R Gene Mutation in the Biallelic State Leading to Fatal Childhood Neurodegeneration." Neuropediatrics 51, no. 04 (May 28, 2020): 302–6. http://dx.doi.org/10.1055/s-0040-1702161.

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AbstractWe report the clinical and molecular characterization of a novel biallelic mutation in the CSF1R gene leading to an autosomal recessive form of childhood onset leukoencephalopathy in a consanguineous family. The female child experienced acute encephalopathy at the age of 2 years, followed by spasticity and loss of all achieved milestones over 6 months. Her elder brother presented with encephalopathy at 4 years of age, with a subsequent loss of all achieved milestones over 8 months. Brain imaging in both children revealed multiple well-defined areas of calcification in the parietal and frontal regions and the occipital horns of both lateral ventricles. Clinical exome trio analysis showed homozygosity for a p.T833M mutation in CSF1R in the girl. Heterozygous family members, including both parents, were asymptomatic, with the eldest being 68 years of age. Total CSF1R protein expression levels were normal as compared with wild-type allele, but CSF1 ligand dependent autophosphorylation was consistent with a hypomorphic allele.

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Bereznai, Benjamin, Anita Trauninger, Ilona György, Katalin Szakszon, Zsuzsanna Almássy, Endre Pál, Ágnes Herczegfalvi, Katalin Várdi Visy, Zsolt Illés, and Mária Judit Molnár. "Clinical manifestation, disease course and response to enzyme replacement therapy in Hungarian patients with Pompe’s disease." Orvosi Hetilap 152, no. 39 (September 2011): 1569–75. http://dx.doi.org/10.1556/oh.2011.29184.

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Pompe’s disease is an autosomal recessive disease caused by deficiency of acid-alpha-glucosidase. Aims and Methods: Authors analyzed the phenotype of 11 Hungarian patients with Pompe’s disease and evaluated clinical parameters and response to enzyme replacement therapy during a long-term follow-up in 8 patients. Results: One patient with atypical infantile form presented with cardiomyopathy and a very slow progression of motor deficits; after 2 years of enzyme replacement therapy no disability was present at the age 6 years. Another patient was asymptomatic at the age of 2.5 years. The adult onset form was characterized by slight to prominent limb-girdle myopathy with an age of onset between 20 and 50 years. In 3 of such cases respiratory insufficiency was also present. Conclusions: Hungarian patients with Pompe’s disease presented with a wide phenotypic variability ranging from atypical early childhood form with slowly progressive course to late-onset limb-girdle myopathy with variable courses. Enzyme replacement therapy resulted in significant improvement in motor and respiratory functions in most of the patients. Orv. Hetil., 2011, 152, 1569–1575.

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Tanner, Caroline M., Biao Chen, Wen-Zhi Wang, Man-Ling Peng, Zho-Lin Liu, Xue-Ling Liang, Li Chiung Kao, David W. Gilley, and Bruce S. Schoenberg. "Environmental Factors in the Etiology of Parkinson's Disease." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 14, S3 (August 1987): 419–23. http://dx.doi.org/10.1017/s0317167100037835.

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ABSTRACT:Parkinson's disease (PD) has been proposed to result from the interaction of aging and environment in susceptible individuals. Defective metabolism of debrisoquine, inherited as an autosomal recessive, has been associated with this susceptibility. In 35 PD patients and 19 age-matched controls, no significant differences in debrisoquine metabolism were found, although a trend to impaired metabolism was noted in patients with disease onset ≤40. Foci of PD patients were associated with rural living and well water drinking, or rural living coupled with market gardening or wood pulp mills. In a questionnaire survey, patients with PD onset ≤age 47 were significantly more likely to have lived in rural areas and to have drunk well water than those with onset ≥age 54 (p≤0.01). Because of population mobility in North America, a case-control study designed to test environmental, occupational, dietary and other proposed risk factors for PD was conducted in China, where the population is more stationary and the environment more stable. No significant differences in incidences of head trauma, smoking or childhood measles were found between patients and controls.

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Maystadt, Isabelle, René Rezsöhazy, Martine Barkats, Sandra Duque, Pascal Vannuffel, Sophie Remacle, Barbara Lambert, et al. "The Nuclear Factor κB–Activator Gene PLEKHG5 Is Mutated in a Form of Autosomal Recessive Lower Motor Neuron Disease with Childhood Onset." American Journal of Human Genetics 81, no. 1 (July 2007): 67–76. http://dx.doi.org/10.1086/518900.

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Banu, Selina Husna, and Mashaya Zaman Koli. "Progressive Myoclonic Epilepsy: Review Article with A Case Report of Lafora Disease." Bangladesh Journal of Child Health 42, no. 3 (December 17, 2018): 138–47. http://dx.doi.org/10.3329/bjch.v42i3.39269.

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Progressive myoclonic epilepsy (PME) is an autosomal recessive, apparently a rare complex epilepsy syndrome. Among different types of PME, lafora body disease is more quickly progressive usually fatal within 2nd and 3rd decade. They are characterized by childhood or adolescent onset difficult to control multiple type seizures including myoclonous, generalized tonic clonic, absences, psychomotor regression with ataxia, dementia, dysarthria, visual hallucinations, and other general features. Early suspicion is important that leads to the rational diagnostic workout. The electro-clinical criteria would help a lot to exclude the benign epilepsy syndrome such as juvenile myoclonic epilepsy (JME) and suspect PME at the early stage of the complex epilepsy syndrome. Diagnosis is further clarified and confirmed by finding lafora body in skin and genetic study. Genetic mutation found in more than 87% cases in EPM2A gene or the EPM2B also known as NHLRC1 gene and are inherited in an autosomal recessive manner. EMP2A gene is located on chromosome 6q24. They are reported from Mediterranean basin, central Asia, India, Pakistan, northern Africa and Middle East where consanguineous marriage is common. We report a diagnosed case for the first time in Bangladesh. With the detail clinical history, rational use of the available investigation tools and clinical suspicion, diagnosis of the disorder at its early stage is possible. The rapid progress in genetic therapy would be a great hope in near future. Bangladesh J Child Health 2018; VOL 42 (3) :138-147

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Byun, Minji, Cindy S. Ma, Arzu Akçay, Vincent Pedergnana, Umaimainthan Palendira, Jinjong Myoung, Danielle T. Avery, et al. "Inherited human OX40 deficiency underlying classic Kaposi sarcoma of childhood." Journal of Experimental Medicine 210, no. 9 (July 29, 2013): 1743–59. http://dx.doi.org/10.1084/jem.20130592.

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Kaposi sarcoma (KS), a human herpes virus 8 (HHV-8; also called KSHV)–induced endothelial tumor, develops only in a small fraction of individuals infected with HHV-8. We hypothesized that inborn errors of immunity to HHV-8 might underlie the exceedingly rare development of classic KS in childhood. We report here autosomal recessive OX40 deficiency in an otherwise healthy adult with childhood-onset classic KS. OX40 is a co-stimulatory receptor expressed on activated T cells. Its ligand, OX40L, is expressed on various cell types, including endothelial cells. We found OX40L was abundantly expressed in KS lesions. The mutant OX40 protein was poorly expressed on the cell surface and failed to bind OX40L, resulting in complete functional OX40 deficiency. The patient had a low proportion of effector memory CD4+ T cells in the peripheral blood, consistent with impaired CD4+ T cell responses to recall antigens in vitro. The proportion of effector memory CD8+ T cells was less diminished. The proportion of circulating memory B cells was low, but the antibody response in vivo was intact, including the response to a vaccine boost. Together, these findings suggest that human OX40 is necessary for robust CD4+ T cell memory and confers apparently selective protective immunity against HHV-8 infection in endothelial cells.

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Dudipala, Sai Chandar, Naveen Reddy Cheruku, and Krishna Chaithanya Battu. "Hereditary spastic paraplegia associated with a rare endoplasmic reticulum lipid raft-associated protein 2 mutation." International Journal of Contemporary Pediatrics 7, no. 10 (September 21, 2020): 2077. http://dx.doi.org/10.18203/2349-3291.ijcp20204055.

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Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurological disorders that are characterized by progressive spasticity of the lower extremities. It can present as pure form or complex form. It can be present from infancy to adulthood, but majority in adult population. Childhood onset HSP must be differentiated from common conditions like cerebral palsy, neurodegenerative disorders and metabolic disorders. Many patients with pediatric HSP are mistakenly diagnosed with cerebral palsy. In children with spastic paraplegia in whom no acquired cause identified, HSP should be considered. Here we diagnosed a 6-year-old boy with HSP who presented with progressive spastic paraplegia, intellectual disability, seizures, joint contractures and cataract. His genetic study revealed exonic deletion of endoplasmic reticulum lipid raft-associated protein gene, which is associated with complicated Autosomal recessive HSP 18 (SPG18). HSP 18 was rarely described in literature.

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Lebedenko, A. A., S. B. Berezhanskay, A. S. Todorova, N. N. Vostrykh, E. Y. Kaushanskay, E. A. Lukyanova, E. A. Papsheva, G. N. Smykova, and L. N. Taranenko. "A rare case of type i glutaric aciduria in an early child." Medical Herald of the South of Russia 11, no. 4 (December 20, 2020): 84–91. http://dx.doi.org/10.21886/2219-8075-2020-11-4-84-91.

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Glutaric aciduria type I (deficiency of glutaryl-COA dehydrogenase, glutaric acidemia type I) is a rare autosomal recessive disease caused by mutations in the gene encoding the enzyme glutaryl – COA - dehydrogenase (GCDH). Cerebral organic aciduria, caused by a deficiency of glutaryl-COA - dehydrogenase, is generally considered a neurological disorder.The phenotypic spectrum of untreated GA-1 varies from a more common and pronounced form (a disease with infancy) to a low-symptom and less common form. In people with the same genotype, the clinical manifestations and depth of CNS damage can vary widely depending on the age of manifestation of acute encephalopathic crises. It is assumed that with early detection and treatment of “asymptomatic” newborns (in the context of screening for this disease), most people who would have developed manifestations of GA-1 with childhood or late onset will remain asymptomatic.

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Maystadt, I., R. Rezsöhazy, M. Barkats, S. Duque, P. Vannuffel, M. Najimi, A. Munnich, L. Viollet, and C. Verellen-Dumoulin. "G.O.4 The NF-kappaB activator PLEKHG5 gene is mutated in a form of autosomal recessive lower motor neuron disease with childhood onset." Neuromuscular Disorders 17, no. 9-10 (October 2007): 767. http://dx.doi.org/10.1016/j.nmd.2007.06.025.

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Pojskic, Lejla, Ismet Gavrankapetanovic, Naida Lojo-Kadric, Rifat Hadziselimovic, and Kasim Bajrovic. "A genotyping assay for missense mutation in WISP3 gene associated with childhood onset pseudorheumatoid arthropathy." Journal of Health Sciences 5, no. 2 (September 29, 2015): 59–64. http://dx.doi.org/10.17532/jhsci.2015.241.

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Introduction: Progressive pseudorheumatoid dysplasia (PPD) is an autosomal recessive genetic disorder reported to be caused by gene alterations of the Wnt1-inducible signaling pathway protein 3 corresponding gene (WISP3) located on chromosome position 6q22. Up to date, there is only a handful of WISP3 mutations identified in Europe, whereas most mutations are identified in Asia and Middle East. According to our knowledge, this is the first report of genetic dissection of WISP3 associated with spondyloepiphyseal dysplasia tarda from Bosnia and Herzegovina. Based on clinical examination findings (general manifestations, physical examination, characteristics of their bones on X-ray and laboratory results), an index patient was directed to WISP3 genotyping for confirmation of suspected diagnosis of PPD.Methods: DNA was extracted from peripheral blood leukocytes. All 5 exons and their exon-intron boundaries of the WISP3 gene were amplified by polymerase chain reaction (PCR) and sequenced by Sanger method. Segregation analysis was done to confirm the familial carrier status.Results: A missense mutation (C223G) - homozygous T to G transition at c.667 in exon 4 was identified in index patient. This mutation changed codon CAG to TAG and resulted in a subsequent change of the cysteine to glycine codon. Same mutation was observed in both parents in heterozygous form confirming the familial segregation.Conclusion: Due to its nature, the identified mutation C223G in exon 4 in WISP3 gene is the most probably causative for PPD in described patient. Here we describe the PCR based method for genotyping of specific mutation in WISP3 gene. The identification of this mutation might be a valuable addition to a regional databases on rare genetic variant although a functional analysis should be performed to explain its pathological effect.

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Tanabe, Fuminori, Hirotake Kasai, Michiko Morimoto, Shigeharu Oh, Hidetoshi Takada, Toshiro Hara, and Masahiko Ito. "Novel HeterogenousCHS1Mutations Identified in Five Japanese Patients with Chediak-Higashi Syndrome." Case Reports in Medicine 2010 (2010): 1–5. http://dx.doi.org/10.1155/2010/464671.

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Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder characterized by oculocutaneous albinism, recurrent bacterial infections and progressive neurological dysfunction. We demonstrate novel heterogenous mutations ofCHS1, the responsive gene of CHS, identified in five Japanese patients with CHS. Patients 1, 2, and 3 were siblings, and they had albinism of the skin and hair. They all had a heterogenous two-base deletion (c.5541-5542 del AA, p.Q1847fsX1850) in exon 18. Patient 4 had a heterogenous single-base insertion (c.3944-3945 ins C, p.T1315fsX1331) in exon 10. The patient exhibited severe early-onset phenotype and suffered from hemophagocytic lymphohistiocytosis. Patient 5 had two heterogenous nonsense mutations; c.7982C>G, p.S2661X in exon 30 and c.8281A>T, p.R2761X in exon 31. The patient suffered from infections in childhood and had visual disturbance and albinism of the skin and hair. TheCHS1mutations described here have not been reported previously.

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Garone, Caterina, Robert W. Taylor, Andrés Nascimento, Joanna Poulton, Carl Fratter, Cristina Domínguez-González, Julie C. Evans, et al. "Retrospective natural history of thymidine kinase 2 deficiency." Journal of Medical Genetics 55, no. 8 (March 30, 2018): 515–21. http://dx.doi.org/10.1136/jmedgenet-2017-105012.

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BackgroundThymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive TK2 mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy.ObjectiveTo perform a retrospective natural history study of a large cohort of patients with TK2 deficiency.MethodsThe study was conducted by 42 investigators across 31 academic medical centres.ResultsWe identified 92 patients with genetically confirmed diagnoses of TK2 deficiency: 67 from literature review and 25 unreported cases. Based on clinical and molecular genetics findings, we recognised three phenotypes with divergent survival: (1) infantile-onset myopathy (42.4%) with severe mitochondrial DNA (mtDNA) depletion, frequent neurological involvement and rapid progression to early mortality (median post-onset survival (POS) 1.00, CI 0.58 to 2.33 years); (2) childhood-onset myopathy (40.2%) with mtDNA depletion, moderate-to-severe progression of generalised weakness and median POS at least 13 years; and (3) late-onset myopathy (17.4%) with mild limb weakness at onset and slow progression to respiratory insufficiency with median POS of 23 years. Ophthalmoparesis and facial weakness are frequent in adults. Muscle biopsies show multiple mtDNA deletions often with mtDNA depletion.ConclusionsIn TK2 deficiency, age at onset, rate of weakness progression and POS are important variables that define three clinical subtypes. Nervous system involvement often complicates the clinical course of the infantile-onset form while extraocular muscle and facial involvement are characteristic of the late-onset form. Our observations provide essential information for planning future clinical trials in this disorder.

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Jo, Dong Hyun, Dong Woo Song, Chang Sik Cho, Un Gi Kim, Kyu Jun Lee, Kihwang Lee, Sung Wook Park, et al. "CRISPR-Cas9–mediated therapeutic editing of Rpe65 ameliorates the disease phenotypes in a mouse model of Leber congenital amaurosis." Science Advances 5, no. 10 (October 2019): eaax1210. http://dx.doi.org/10.1126/sciadv.aax1210.

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Leber congenital amaurosis (LCA), one of the leading causes of childhood-onset blindness, is caused by autosomal recessive mutations in several genes including RPE65. In this study, we performed CRISPR-Cas9–mediated therapeutic correction of a disease-associated nonsense mutation in Rpe65 in rd12 mice, a model of human LCA. Subretinal injection of adeno-associated virus carrying CRISPR-Cas9 and donor DNA resulted in >1% homology-directed repair and ~1.6% deletion of the pathogenic stop codon in Rpe65 in retinal pigment epithelial tissues of rd12 mice. The a- and b-waves of electroretinograms were recovered to levels up to 21.2 ± 4.1% and 39.8 ± 3.2% of their wild-type mice counterparts upon bright stimuli after dark adaptation 7 months after injection. There was no definite evidence of histologic perturbation or tumorigenesis during 7 months of observation. Collectively, we present the first therapeutic correction of an Rpe65 nonsense mutation using CRISPR-Cas9, providing new insight for developing therapeutics for LCA.

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Karle, Stephanie M., Barbara Uetz, Vera Ronner, Lisa Glaeser, Friedhelm Hildebrandt, and Arno Fuchshuber. "Novel Mutations in NPHS2 Detected in Both Familial and Sporadic Steroid-Resistant Nephrotic Syndrome." Journal of the American Society of Nephrology 13, no. 2 (February 2002): 388–93. http://dx.doi.org/10.1681/asn.v132388.

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ABSTRACT. Autosomal recessive steroid-resistant nephrotic syndrome (SRINS) belongs to the heterogeneous group of familial nephrotic syndrome and represents a frequent cause of end-stage renal disease in childhood. This kidney disorder is characterized by early onset of proteinuria, progression to end-stage renal disease, and histologic findings of focal segmental glomerulosclerosis, minimal change nephrotic syndrome, or both. A causative gene, NPHS2, has been mapped to chromosome 1q25-q31 and was recently identified by positional cloning. This study reports five novel NPHS2 mutations: A284V, R196P, V290M, IVS4-1G→T, and 460-467insT in 12 (46%) of 26 multiplex families and in 7 (28%) of 25 single patients with the clinical diagnosis of a SRINS. Because NPHS2 mutations were found in nearly 30% of these patients with “sporadic” SRINS, mutational analysis should also be performed in these patients. Besides better classification of the disease entity, identification of NPHS2 mutations may save some of these patients from unnecessary steroid treatment and also permit the prediction of absence of disease recurrence after kidney transplantation.

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Rajib, Dutta. "Endocannabinoidome and its role in neurological disorders-A comprehensive update of existing literature." Journal of Neuroscience and Neurological Disorders 5, no. 1 (June 9, 2021): 048–54. http://dx.doi.org/10.29328/journal.jnnd.1001050.

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Mitochondrial and lysosomal dysfunction accounts for a large group of inherited metabolic disorders most of which are due to a dysfunctional mitochondrial respiratory chain (MRC) leading to deficient energy production and defects in phagocytosis in endosomal-lysosomal pathway respectively. MRC function depends on the coordinated expression of both nuclear (nDNA) and mitochondrial (mtDNA) genomes. Thus, mitochondrial diseases can be caused by genetic defects in either the mitochondrial or the nuclear genome, or in the cross-talk between the two. The mitochondrial DNA depletion syndromes (MDSs) are a clinically heterogeneous group of disorders with an autosomal recessive pattern of inheritance that have onset in infancy or early childhood and are characterized by a reduced number of copies of mtDNA in affected tissues and organs. In this review article, we summarized the spectrum of mtDNA depletion disorders along with minor learning of lysosomal storage diseases. This current article offers a perspective on the role of genetics in medical practice and how this role may evolve over the next several years.

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Guerrero-Valero, Marta, Federica Grandi, Silvia Cipriani, Valeria Alberizzi, Roberta Di Guardo, Gaetan Chicanne, Linda Sawade, et al. "Dysregulation of myelin synthesis and actomyosin function underlies aberrant myelin in CMT4B1 neuropathy." Proceedings of the National Academy of Sciences 118, no. 10 (March 2, 2021): e2009469118. http://dx.doi.org/10.1073/pnas.2009469118.

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Charcot-Marie-Tooth type 4B1 (CMT4B1) is a severe autosomal recessive demyelinating neuropathy with childhood onset, caused by loss-of-function mutations in the myotubularin-related 2 (MTMR2) gene. MTMR2 is a ubiquitously expressed catalytically active 3-phosphatase, which in vitro dephosphorylates the 3-phosphoinositides PtdIns3P and PtdIns(3,5)P2, with a preference for PtdIns(3,5)P2. A hallmark of CMT4B1 neuropathy are redundant loops of myelin in the nerve termed myelin outfoldings, which can be considered the consequence of altered growth of myelinated fibers during postnatal development. How MTMR2 loss and the resulting imbalance of 3′-phosphoinositides cause CMT4B1 is unknown. Here we show that MTMR2 by regulating PtdIns(3,5)P2 levels coordinates mTORC1-dependent myelin synthesis and RhoA/myosin II-dependent cytoskeletal dynamics to promote myelin membrane expansion and longitudinal myelin growth. Consistent with this, pharmacological inhibition of PtdIns(3,5)P2 synthesis or mTORC1/RhoA signaling ameliorates CMT4B1 phenotypes. Our data reveal a crucial role for MTMR2-regulated lipid turnover to titrate mTORC1 and RhoA signaling thereby controlling myelin growth.

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Kurth, Ingo, Debra A. Thompson, Klaus Rüther, Kecia L. Feathers, Jared D. Chrispell, Jana Schroth, Christina L. McHenry, et al. "Targeted Disruption of the Murine Retinal Dehydrogenase Gene Rdh12 Does Not Limit Visual Cycle Function." Molecular and Cellular Biology 27, no. 4 (November 27, 2006): 1370–79. http://dx.doi.org/10.1128/mcb.01486-06.

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ABSTRACT RDH12 codes for a member of the family of short-chain alcohol dehydrogenases/reductases proposed to function in the visual cycle that supplies the chromophore 11-cis retinal to photoreceptor cells. Mutations in RDH12 cause severe and progressive childhood onset autosomal-recessive retinal dystrophy, including Leber congenital amaurosis. We generated Rdh12 knockout mice, which exhibited grossly normal retinal histology at 10 months of age. Levels of all-trans and 11-cis retinoids in dark- and light-adapted animals and scotopic and photopic electroretinogram (ERG) responses were similar to those for the wild type, as was recovery of the ERG response following bleaching, for animals matched for an Rpe65 polymorphism (p.L450M). Lipid peroxidation products and other measures of oxidative stress did not appear to be elevated in Rdh12 −/− animals. RDH12 was localized to photoreceptor inner segments and the outer nuclear layer in both mouse and human retinas by immunohistochemistry. The present findings, together with those of earlier studies showing only minor functional deficits in mice deficient for Rdh5, Rdh8, or Rdh11, suggest that the activity of any one isoform is not rate limiting in the visual response.

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Drutman, Scott B., Filomeen Haerynck, Franklin L. Zhong, David Hum, Nicholas J. Hernandez, Serkan Belkaya, Franck Rapaport, et al. "Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis." Proceedings of the National Academy of Sciences 116, no. 38 (September 4, 2019): 19055–63. http://dx.doi.org/10.1073/pnas.1906184116.

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Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop JRRP following exposure to these common viruses. We report 2 siblings with a syndromic form of JRRP associated with mild dermatologic abnormalities. Whole-exome sequencing of the patients revealed a private homozygous mutation in NLRP1, encoding Nucleotide-Binding Domain Leucine-Rich Repeat Family Pyrin Domain-Containing 1. We find the NLRP1 mutant allele to be gain of function (GOF) for inflammasome activation, as demonstrated by the induction of inflammasome complex oligomerization and IL-1β secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1β at baseline. Finally, both patients displayed elevated levels of inflammasome-induced cytokines in the serum. Six NLRP1 GOF mutations have previously been described to underlie 3 allelic Mendelian diseases with differing phenotypes and modes of inheritance. Our results demonstrate that an autosomal recessive, syndromic form of JRRP can be associated with an NLRP1 GOF mutation.

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Fogli, A., and O. Boespflug-Tanguy. "The large spectrum of eIF2B-related diseases." Biochemical Society Transactions 34, no. 1 (January 20, 2006): 22–29. http://dx.doi.org/10.1042/bst0340022.

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eIF2B (eukaryotic initiation factor 2B) is a GEF (guanine nucleotide-exchange factor) that plays, with its substrate eIF2, a key regulatory role in the translation initiation phase of protein synthesis. The importance of correct control of eIF2 and eIF2B for normal physiology is underlined by the recent involvement of the five genes that encode the five eIF2B subunits in a severe autosomal recessive neurodegenerative disease, described in young children as CACH (childhood ataxia with central nervous system hypomyelination)/VWM (leukoencephalopathy with vanishing white matter) syndrome. The syndrome is characterized by episodes of rapid deterioration during febrile illnesses or following head trauma and symmetrical demyelination of the brain white matter with cavitation aspects, leading to a progressive vanishing of the white matter replaced by CSF (cerebrospinal fluid). However, a wide clinical spectrum has been observed in the 148 patients presently reported, from congenital forms with rapid death to adult-onset forms with slow mental decline and progressive motor dysfunction, sometimes associated with congenital eye abnormalities or ovariodysgenesis. So far, 77 different mutations in each of the five EIF2B genes (EIF2B1–5), encoding subunits eIF2Bα–ϵ, have been found, with two-thirds affecting the eIF2Bϵ subunit. The correlation found between the level of GEF activity of eIF2B in the mutated white blood cells and the age at disease onset suggests a direct role of the abnormal translation control in the pathophysiology of the disease.

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Alfadhel, Majid, Sandra Sirrs, Paula J. Waters, András Szeitz, Eduard Struys, Marion Coulter-Mackie, and Sylvia Stockler-Ipsiroglu. "Variability of Phenotype in Two Sisters with Pyridoxine Dependent Epilepsy." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 39, no. 4 (July 2012): 516–19. http://dx.doi.org/10.1017/s0317167100014050.

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Background:Pyridoxine dependent epilepsy (PDE) is characterized by neonatal epileptic encepahalopathy responsive to pharmacological doses of vitamin B6. Recently an autosomal recessive deficiency in Antiquitin (ALDH7A1), a gene involved in the catabolism of lysine has been identified as the underlying cause.Case report:In 21 and 23 year-old sisters, who had presented with neonatal / early infantile onset seizures, PDE was confirmed by elevated urinary alpha aminoadipic- 6- semialdehyde (α-AASA) excretion and compound heterozygosity for two known ALDH7A1 missense mutations. Although epilepsy was well controlled upon treatment with pyridoxine, thiamine, phenytoin and carbamazepine since early infancy, both had developmental delay with prominent speech delay as children. As adults, despite the same genetic background and early treatment with pyridoxine, their degree of intellectual disability (ID) differed widely. While the older sister's cognitive functions were in the moderate ID range and she was not able to live unattended, the younger sister had only mild ID and was able to live independently.Conclusion:Although seizures are a defining feature of PDE, other disease manifestations can vary widely even within the same family. Adult neurologists should be aware that the diagnosis of PDE can be delayed and PDE should be considered in the differential diagnosis of adults with seizure disorders dating from childhood.

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Stahl, Mirjam, Eva Steinke, and Marcus A. Mall. "Quantification of Phenotypic Variability of Lung Disease in Children with Cystic Fibrosis." Genes 12, no. 6 (May 25, 2021): 803. http://dx.doi.org/10.3390/genes12060803.

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Cystic fibrosis (CF) lung disease has the greatest impact on the morbidity and mortality of patients suffering from this autosomal-recessive multiorgan disorder. Although CF is a monogenic disorder, considerable phenotypic variability of lung disease is observed in patients with CF, even in those carrying the same mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or CFTR mutations with comparable functional consequences. In most patients with CF, lung disease progresses from childhood to adulthood, but is already present in infants soon after birth. In addition to the CFTR genotype, the variability of early CF lung disease can be influenced by several factors, including modifier genes, age at diagnosis (following newborn screening vs. clinical symptoms) and environmental factors. The early onset of CF lung disease requires sensitive, noninvasive measures to detect and monitor changes in lung structure and function. In this context, we review recent progress with using multiple-breath washout (MBW) and lung magnetic resonance imaging (MRI) to detect and quantify CF lung disease from infancy to adulthood. Further, we discuss emerging data on the impact of variability of lung disease severity in the first years of life on long-term outcomes and the potential use of this information to improve personalized medicine for patients with CF.

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Waheed, Nadia, Anjum Saeed, Sadaqat Ijaz, Zafar Fayyaz, Muhammad Nadeem Anjum, Yasir Zahoor, and Huma Arshad Cheema. "Variability of clinical and biochemical phenotype in liver phosphorylase kinase deficiency with variants in the phosphorylase kinase (PHKG2) gene." Journal of Pediatric Endocrinology and Metabolism 33, no. 9 (September 25, 2020): 1117–23. http://dx.doi.org/10.1515/jpem-2019-0603.

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AbstractBackgroundPHKG2-related liver phosphorylase kinase deficiency is inherited in autosomal recessive pattern and is a rare type of liver glycogenosis. We demonstrated the clinical presentation and genetic determinants involved in children with PHKG2- related liver phosphorylase kinase deficiency.MethodologyTen Pakistani children with liver phosphorylase kinase from seven different families, were enrolled over a period of 18 months. All regions of the PHKG2 gene spanning exons and splicing sites were evaluated through targeted exome sequencing. Variants were analyzed using different bioinformatics tools. Novel variants were reconfirmed by direct sequencing.ResultsSeven different variants were identified in PHKG2 gene including five novel variants: three stop codons (c.226C>T [p.R76*], c.454C>T [p.R152*] and c.958C>T [p.R320*]), one missense variant c.107C>T (p.S36F) and one splice site variant (c.557-3C>G). All five novel variants were predicted to be damaging by in Silico analysis. The variants are being transmitted through recessive pattern of inheritance except one family (two siblings) has compound heterozygotes. Laboratory data revealed elevated transaminases and triglycerides, normal creatinine phosphokinase and uric acid levels but with glycogen loaded hepatocytes on liver histology.ConclusionPHKG2 related liver phosphorylase kinase deficiency can mimic both liver glycogenosis type I (glucose-6-phosphatase deficiency) & III(amylo-1,6 glucosidase) and characterized by early childhood onset of hepatomegaly, growth restriction, elevated liver enzymes and triglycerides. Molecular analysis would be helpful in accurate diagnosis and proper treatment. The symptoms and biochemical abnormalities in liver glycogenosis due phosphorylase kinase deficiency tend to improve with proper dietary restrictions but need to be monitored for long-term complications such as liver fibrosis and cirrhosis.

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Journal articles on the topic 'Childhood onset; Autosomal recessive; Neurones'

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