Littérature scientifique sur le sujet « Hypomyelinating »

Leukodystrophies are a group of hereditary progressive diseases of the central nervous system characterized by selective lesions in white matter with specific involvement of glial cells. There are hypomyelinating (absence of myelin deposition), demyelinating (loss of previously deposited myelin), dysmyelinating (deposition of structurally or biochemically abnormal myelin), and myelinolytic leukodystrophies (myelin vacuolization). Hypomyelinating leukodystrophies (HL), like most leukodystrophies, debut in childhood or adolescence and are characterized by a progressive course of the disease. HL occurs as a result of impaired synthesis of proteins responsible for the development, structure, and integrity of the myelin sheath, involved in the processes of transcription and translation. In the latter group, the main role is assigned to HL associated with biallelic mutations in the genes of the RNA polymerase III transcription complex, POLR3: POLR3A, POLR3B, POLR1C, and POLR3K. The diagnosis can be confirmed by magnetic resonance imaging of the brain. POLR3A-associated HL is manifested by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. The magnetic resonance features of POLR3-associated HL include diffuse hypomyelination with relative preservation of the dentate nuclei, anterolateral nuclei of the thalamus, globus pallidus, pyramidal tracts at the level of the posterior part of the internal capsules, and the corona radiata. In some cases, thinning of the corpus callosum and atrophy of the cerebellum were also noted. The article presents a clinical case of a patient with POL3A-associated HL with spinal cord injury with the debut in early childhood.

Leukodystrophies and genetic leukoencephalopathies are a heterogeneous group of heritable disorders that affect the glial-axonal unit. As more patients with unsolved leukodystrophies and genetic leukoencephalopathies undergo next generation sequencing, causative mutations in genes leading to central hypomyelination are being identified. Two such individuals presented with arthrogryposis multiplex congenita, congenital hypomyelinating neuropathy, and central hypomyelination with early respiratory failure. Whole exome sequencing identified biallelic mutations in the CNTNAP1 gene: homozygous c.1163G>C (p.Arg388Pro) and compound heterozygous c.967T>C (p.Cys323Arg) and c.319C>T (p.Arg107*). Sural nerve and quadriceps muscle biopsies demonstrated progressive, severe onion bulb and axonal pathology. By ultrastructural evaluation, septate axoglial paranodal junctions were absent from nodes of Ranvier. Serial brain magnetic resonance images revealed hypomyelination, progressive atrophy, and reduced diffusion in the globus pallidus in both patients. These 2 families illustrate severe progressive peripheral demyelinating neuropathy due to the absence of septate paranodal junctions and central hypomyelination with neurodegeneration in CNTNAP1-associated arthrogryposis multiplex congenita.

Background: Biallelic variants in POLR1C are associated with POLR3-related leukodystrophy (POLR3-HLD), or 4H leukodystrophy (Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism), and Treacher Collins syndrome (TCS). The clinical spectrum of POLR3-HLD caused by variants in this gene has not been described. Methods: A cross-sectional observational study involving 25 centers worldwide was conducted between 2016 and 2018. The clinical, radiologic and molecular features of 23 unreported and previously reported cases of POLR3-HLD caused by POLR1C variants were reviewed. Results: Most participants presented between birth and age 6 years with motor difficulties. Neurological deterioration was seen during childhood, suggesting a more severe phenotype than previously described. The dental, ocular and endocrine features often seen in POLR3-HLD were not invariably present. Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including one individual with clear TCS features. Several cases did not exhibit all the typical radiologic characteristics of POLR3-HLD. A total of 29 different pathogenic variants in POLR1C were identified, including 13 new disease-causing variants. Conclusions: Based on the largest cohort of patients to date, these results suggest novel characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.

4H (hypomyelination, hypodontia and hypogonadotropic hypogonadism) leukodystrophy (4H) is an autosomal recessive hypomyelinating white matter (WM) disorder with neurologic, dental, and endocrine abnormalities. The aim of this study was to develop and validate a magnetic resonance imaging (MRI) scoring system for 4H. A scoring system (0–54) was developed to quantify hypomyelination and atrophy of different brain regions. Pons diameter and bicaudate ratio were included as measures of cerebral and brainstem atrophy, and reference values were determined using controls. Five independent raters completed the scoring system in 40 brain MRI scans collected from 36 patients with genetically proven 4H. Interrater reliability (IRR) and correlations between MRI scores, age, gross motor function, gender, and mutated gene were assessed. IRR for total MRI severity was found to be excellent (intraclass correlation coefficient: 0.87; 95% confidence interval: 0.80–0.92) but varied between different items with some (e.g., myelination of the cerebellar WM) showing poor IRR. Atrophy increased with age in contrast to hypomyelination scores. MRI scores (global, hypomyelination, and atrophy scores) significantly correlated with clinical handicap (p < 0.01 for all three items) and differed between the different genotypes. Our 4H MRI scoring system reliably quantifies hypomyelination and atrophy in patients with 4H, and MRI scores reflect clinical disease severity.

ObjectiveTo determine the clinical, radiologic, and molecular characteristics of RNA polymerase III-related leukodystrophy (POLR3-HLD) caused by biallelic POLR1C pathogenic variants.MethodsA cross-sectional observational study involving 25 centers worldwide was conducted. Clinical and molecular information was collected on 23 unreported and previously reported patients with POLR3-HLD and biallelic pathogenic variants in POLR1C. Brain MRI studies were reviewed.ResultsFourteen female and 9 male patients aged 7 days to 23 years were included in the study. Most participants presented early in life (birth to 6 years), and motor deterioration was seen during childhood. A notable proportion of patients required a wheelchair before adolescence, suggesting a more severe phenotype than previously described in POLR3-HLD. Dental, ocular, and endocrine features were not invariably present (70%, 50%, and 50%, respectively). Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including 1 individual with clear Treacher Collins syndrome (TCS) features. Brain MRI revealed hypomyelination in all cases, often with areas of pronounced T2 hyperintensity corresponding to T1 hypointensity of the white matter. Twenty-nine different pathogenic variants (including 12 new disease-causing variants) in POLR1C were identified.ConclusionsThis study provides a comprehensive description of POLR3-HLD caused by biallelic POLR1C pathogenic variants based on the largest cohort of patients to date. These results suggest distinct characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.

Retroterra scientifico Negli adulti circa il 30-40% delle leucoencefalopatie (LKEN) (= malattie della sostanza bianca) non sono diagnosticati. I pazienti che restano non diagnosticati dopo indagini approfondite possono avare forme atipiche di malattie note, sia genetiche che acquisite, oppure nuove malattie che sono più probabilmente di origine genetica. Nel nostro lavoro abbiamo voluto esplorare l’efficienza di un approccio sistematico che include il sequenziamento del DNA con tecniche di nuova generazione (NGS) nella diagnosi di pazienti adulti con LKEN a causa ignota, e descrivere le loro caratteristiche cliniche. Pazienti e Metodi In questo studio osservazionale analitico, abbiamo inizialmente revisionato le caratteristiche cliniche e paracliniche dei pazienti adulti (>=18 anni) con LKEN a causa ignota valutati nell’Unità di Malattie Neurodegenerative e Neurometaboliche Rare dell’Istituto Neurologico “C. Besta”, Milano, Italia, dal 2012 al 2018. Successivamente abbiamo usato un pannello genico per il sequenziamento di 142 geni associati a leucoencefalopatie ereditarie e, in un caso familiare rimasto non diagnosticato abbiamo studiato l’intero esoma. Risultati Abbiamo identificato 57 adulti con LKEN a causa ignota (età media 43 anni, intervallo 18-72; 23 maschi, 53 con esordio tardo-adolescenziale o adulto). Trenta di loro, che abbiamo chiamato «ipomielinizzanti», presentavano un pattern di MRI suggestivo di ipomielinizzazione (lieve iperintensità in T2 e segnale T1 normale), mentre i restanti 27, che abbiamo chiamato «demielinizzanti», avevano un pattern di MRI suggestivo di demielinizzazione (marcata iperintensità in T2 e ipointensità in T1). In 13 soggetti ipomielinizzati il pannello genico ha identificato i seguenti geni: POLR3A (n = 2), POLR1C, TUBB4A, RARS1, GJA1, PLP1, GJC2, TBCD, CYP7B1, SPG11, PEX3, e PEX13, mentre in due altri pazienti lo studio dell’esoma ha portato all’identificazione di un nuovo gene malattia. Al contrario, il pannello genico ha permesso la diagnosi di un solo paziente demielinizzante (aciduria metilglutaconica associata al gene AUH). In due altri pazienti la diagnosi è stata posta o con l’analisi diretta di un singolo gene-malattia dopo revisione dei dati clinico-neuroradiologici (leucodistrofia metacromatica associata al gene PSAP) o con una biopsia di cute dopo la negatività del pannello genico (malattia da inclusi intranucleari neuronali, NIID). Tre pazienti (uno ipomielinizzante, due demielinizzanti) avevano malattie acquisite che mimavano una leucodistrofia: una vasculite primaria diagnostica con la biopsia cerebrale senza analisi genetiche e rare varianti di sclerosi multipla, diagnosticate dopo la negatività del pannello. Infine, in otto pazienti con una LKEN scoperta incidentalmente che sono rimasti senza manifestazioni cliniche per anni, il pannello genico ha dato esito negativo. Conclusioni Negli adulti un pattern ipomielinizzante caratterizza un gran numero (circa il 50%) di LKEN a causa ignota. Le LKEN ipomielinizzanti ad esordio tardivo sono molto più comunemente dovute a geni associati alle forme precoci, come POLR3A e TUBB4A, o possono essere dovute a geni associati a paraplegie spastiche ereditarie, come CYP7B1 e SPG11, a geni associati a disordini perossisomiali, come PEX3 e PEX13, o anche a nuovi geni malattia. Fra le forme demielinizzanti solo molto poche sono diagnosticate con un pannello genico se i dati clinico-paraclinici non orientano verso una diagnosi specifica. Occasionalmente, varianti atipiche di malattie acquisite della sostanza bianca possono mimare una LKEN genetica con caratteristiche demielinizzanti o ipomielinizzanti alla risonanza. Infine, un sottogruppo di LKEN demielinizzanti caratterizzato dalla mancanza di manifestazioni cliniche e dall’assenza di mutazioni in geni associati a forme note di LKEN può costituire una nuova entità che abbiamo chiamato leucoencefalopatia diffusa subclinica.
Background In adults, many cases (about 30-40%) of leukoencephalopathies (LKENs), i.e. white matter (WM) diseases, are without definitive diagnosis. Patients who remain undiagnosed despite extensive investigations may have atypical forms of known acquired or genetic diseases, or novel diseases more likely genetic in nature. Aims of our work were to explore the efficiency of a systematic approach, including next generation sequencing (NGS), in the diagnosis of a cohort of adult patients with LKEN of unknown cause, and to describe their clinical features. Patients and Methods In this analytical observation study, we first reviewed the clinical and laboratory features of the adult patients (age >= 18 years) with undiagnosed LKEN assessed at the Unit of Rare Neurodegenerative and Neurometabolic Diseases of the Istituto Neurologico “C. Besta”, Milan, Italy, from 2012 to 2018. A targeted-gene panel sequencing (TGPS) was subsequently used to investigate 142 genes responsible for genetic LKENs, and a whole-exome sequencing (WES) was performed in one familial case remained undiagnosed. Results We identified 57 adult patients with LKEN of unknown cause (mean age 43 years, range 18-72; 23 males; 53 with late-adolescence or adult-onset). Thirty of them, henceforward called hypomyelinating leukoencephalopathies (HypoLKENs), presented an MRI pattern suggestive of hypomyelination (mild T2-hyperintensity and normal T1 signal), whereas the remaining 27 (henceforward called demyelinating leukoencephalopathies, DemLKENs) had an MRI pattern suggestive of demyelination (prominent T2-hyperintensity and prominent T1-hypointensity). In 13 HypoLKENs, TGPS identified the disease-causing genes, i.e., POLR3A (n = 2), POLR1C, TUBB4A, RARS1, GJA1, PLP1, GJC2, TBCD, CYP7B1, SPG11, PEX3, and PEX13, while in two further patients, WES led to the identification of a novel disease-causing gene (preliminarily called GENE_A). In contrast, TGPS identified the disease-causing gene (i.e., AUH) in only one (out of 27) DemLKEN patient affected by methylglutaconic aciduria type 1. In two other DemLKEN patients, the diagnosis was made on the basis of their clinical and MRI features directly by single gene analysis (PSAP-related metachromatic leukodystrophy), or by skin biopsy after negative results of TGPS (neuronal intranuclear inclusion disease, NIID). Three patients (one with HypoLKEN and two with DemLKEN) had acquired diseases mimicking a leukodystrophy, i.e., a primary cerebral vasculitis (diagnosed by brain biopsy without genetic analyses) and rare variants of multiple sclerosis, diagnosed after negative results of TGPS. Finally, in eight subjects with an incidentally found DemLKEN who remained without clinical manifestations over a long period of time, no mutation was found by TGPS. Conclusions In adults, a hypomyelinating pattern characterizes a large number (about 50%) of LKENs of unknown cause. HypoLKENs are most commonly due to genes causing severe early-onset hypomyelinating leukodystrophies (HLDs), such as POLR3A and TUBB4A, or can be due to genes associated with hereditary spastic paraplegias, such as CYP7B1 and SPG11, peroxisomal biogenesis disorders, such as PEX3 and PEX13, or even novel disease-causing genes. Among the DemLKENs of unknown cause, only very few are diagnosed by TGPS if clinical and paraclinical data pointing toward specific diagnoses are lacking. Occasionally, atypical variants of acquired WM diseases can mimic a genetic leukoencephalopathy with demyelinating or hypomyelinating features on MRI. Finally, a subset of DemLKENs characterized by lack of neurological manifestations and no mutation after comprehensive NGS testing may constitute a novel entity we termed subclinical diffuse leukoencephalopathy (SDL).

A hipomielinização ou leucodistrofia hipomielinizante caracteriza-se por diminuição da produção de mielina e consequente redução significativa e permanente de seu depósito na substância branca cerebral. A ressonância magnética (RM) de encéfalo é essencial para o diagnóstico e revela hipersinal leve a moderado na imagem pesada em T2 e sinal variável na imagem pesada em T1, na dependência da quantidade de mielina formada. Para crianças abaixo de 2 anos de idade, mais de um estudo por RM pode ser necessário para confirmar a ausência de mielinização. As leucodistrofias hipomielinizantes clássicas são: a doença de Pelizaeus-Merzbacher (PMD), a doença de Pelizaeus-Merzbacher símile (PMLD), a síndrome de Cockayne, a síndrome 18q-, e mais recentemente descritas, a hipomielinização com catarata congênita (HCC), a hipomielinização com atrofia dos núcleos da base e cerebelo e a hipomielinização com hipodontia e hipogonadismo hipogonadotrófico (síndrome 4H). O objetivo desta tese foi descrever aspectos clínicos, eletrofisiológicos e de neuroimagem em pacientes com hipomielinização. Vinte e cinco pacientes foram incluídos no estudo, apresentando os seguintes diagnósticos: PMD (5), PMLD (5), HCC (1), síndrome de Cockayne (4), síndrome 18q- (1) e leucodistrofias hipomielinizantes não classificadas (4). A avaliação clínica e por RM foi realizada em todos os pacientes e a maioria destes foram submetidos aos estudos eletrofisiológicos com eletroencefalograma (88%), estudo de neurocondução (84%) e potenciais evocados (84%). Vinte e duas famílias foram envolvidas, com consanguinidade reconhecida em quatro delas. A idade variou de 5-21 anos e o sexo masculino representou 56% da amostra. O quadro neurológico teve início até os 3 anos, habitualmente com nistagmo ou ataxia. Manifestações inespecíficas comumente encontradas foram: curso clínico estático ou lentamente progressivo, atraso do desenvolvimento neuropsicomotor, comprometimento antropométrico, deficiência mental, ataxia, sinais de liberação piramidal, nistagmo e alterações da movimentação ocular. Crises epilépticas e manifestações extrapiramidais foram verificadas com menor frequência. Achados discriminatórios foram: o curso clínico progressivo na síndrome de Cockayne, a piora episódica na síndrome 4H, o nistagmo pendular e o tremor cefálico em PMD e PMLD, os dismorfismos nas síndromes de Cockayne e 18q -, a fotossensibilidade na síndrome de Cockayne, as alterações da dentição e o envolvimento endocrinológico na síndrome 4H. O eletroencefalograma exibiu desorganização difusa da atividade elétrica cerebral em 95% dos pacientes, frequentemente associada à assincronia dos elementos fisiológicos do sono, com ou sem paroxismos epileptiformes. O estudo de neurocondução revelou neuropatia periférica desmielinizante, sensitivo-motora ou puramente motora, em 33% da amostra, incluindo pacientes com HCC, síndrome de Cockayne, síndrome 4H e hipomielinização não classificada. Os potenciais evocados evidenciaram disfunção central das vias visuais (29%), auditivas (57%) e somatossensitivas (67%), sem diferenças entre os grupos. O padrão neurorradiológico de hipomielinização, constante entre os grupos, caracterizou-se por alteração simétrica, difusa, extensa e homogênea da substância branca, com hipersinal em T2 e sinal variável em T1. No entanto, algumas particularidades foram observadas em alguns grupos como: maior mielinização da base em relação ao tegmento da ponte em PMD, em HCC e na síndrome 18q-; maior mielinização do tegmento em relação à base em PMLD; predomínio de mielinização no terço médio ou no esplênio do corpo caloso na síndrome 4H; preservação relativa dos tratos piramidais em PMD e na síndrome 4H; mielinização próxima ao normal no núcleo anterolateral do tálamo em PMD, PMLD e na síndrome 4H; focos de mielinização preservada na síndrome 4H; atrofia moderada a grave no corpo caloso em PMD e PMLD ou em cerebelo e corpo caloso na síndrome 4H; atrofia global acentuada na síndrome de Cockayne e ausência de atrofia na síndrome 18q-. Desta forma, confirmamos a heterogeneidade clínica, eletrofisiológica e de neuroimagem da hipomielinização, com resultados muito similares às descrições originais de cada doença, além de reconhecer padrões clínicos e de neuroimagem específicos para algumas doenças. As principais limitações deste estudo foram o tamanho reduzido da nossa amostra e a ausência de confirmação diagnóstica molecular de alguns pacientes. Com o crescente reconhecimento das leucodistrofias hipomielinizantes, torna-se fundamental a melhor compreensão de sua ampla diversidade etiológica, bem como, de suas diferenças sutis
Hypomyelination or hypomyelinating leukodystrophy is characterized by reduced myelin production, leading to significant and permanent decrease on the amount of myelin on the brain white matter. Brain magnetic resonance imaging (MRI) is essential for its diagnosis and discloses a mild to moderate T2W hypersignal and variable T1W signal, which is dependent on the amount of myelin formed. For children bellow 2 years of age, more than one MRI study might be necessary in order to confirm lack of myelination. Classical hypomyelinating leukodystrophies are: Pelizaeus-Merzbacher disease (PMD), Pelizaeus-Merzbacher-like disease (PMLD), Cockayne syndrome, 18q- syndrome, and the more recently described, hypomyelination and congenital cataract (HCC), hypomyelination with atrophy of the basal ganglia and cerebellum, and hypomyelination with hypodontia and hypogonadotrophic hypogonadism (4H syndrome). The aim of this thesis was to describe clinical, electrophysiological and neuroimaging characteristics of patients with hypomyelination. Twenty-five subjects were included in this study and they presented with the following diagnosis: PMD (5), PMLD (5), HCC (1), Cockayne syndrome (4), 18q- syndrome (1) and unclassified hypomyelinating leukodystrophy (4). Clinical and MRI evaluation were performed in all subjects and most of them were submitted to electrophysiological studies with electroencephalogram (88%), nerve conduction study (84%) and multimodel evoked potentials (84%). Twenty- two families were enrolled and imbreeding was recognized in four of them. The age range was 5 to 21 years and males represented 56% of the sample. The age of onset of neurological symptoms was before 3 years old and was characterized mainly by nystagmus and ataxia. Inespecific manifestations commonly seen were: static or slowly progressive clinical course, neurodevelopmental delay, failure to thrive, mental retardation, ataxia, pyramidal signs, nystagmus and other eye movements abnormalities. Epilepsy and extrapyramidal signs were seldom noticed. Discriminant findings were: progressive clinical decline in Cockayne syndrome, episodic deterioration in 4H syndrome, pendular nystagmus and cephalic tremor in PMD and PMLD, dysmorphisms in Cockayne and 18q- syndromes, photosensitivity in Cockayne syndrome, dentition abnormalities and endocrine involvement in 4H syndrome. Electroencephalogram displayed diffuse disorganization of brain electrical activity in 95% of the patients, frequently associated with asynchrony of sleep physiological elements, with or without epileptiform paroxysms. Nerve conduction study disclosed sensory-motor or purely motor demyelinating peripheral neuropathy in 33% of the sample, including patients with HCC, Cockayne syndrome, 4H syndrome and unclassified hypomyelinating leukodystrophy. Evoked potentials demonstrated central dysfunction of the visual (29%), auditory (57%) and somatosensory (67%) pathways, without discrimination among the groups. Hypomyelination pattern on brain MRI was constant among the groups and was characterized by symmetrical, diffuse, extensive and homogeneous abnormal white matter, displayed by T2W hypersignal and variable T1W signal. Nevertheless, some particular findings were observed in some groups: increased myelination of basilar portion of pons compared to the tegmental region in PMD, HCC and 18q- syndrome; increased tegmental myelination compared to the basilar portion of pons in PMLD; predominant myelination of corpus callosum truncus and splenium in 4H syndrome; relative sparing of pyramidal tract in PMD and 4H syndrome; close to normal myelination in anterolateral nucleus of the thalamus in PMD, PMLD and 4H syndrome; focal areas of preserved myelination in 4H syndrome; moderate to severe atrophy of corpus callosum in PMD and PMLD, and of cerebellum and corpus callosum in 4H syndrome; global and pronounced brain atrophy in Cockayne syndrome, and no brain atrophy in 18q- syndrome. We were able to confirm the clinical, electrophysiological and neuroimaging heterogeneity in hypomyelination, with findings similar to those of the original descriptions, and to recognize specific clinical and neuroimaging patterns in some conditions. The main limitations of this study were the small size of our sample and the absence of molecular confirmation of diagnosis in some of the patients. As hypomyelinating leukodystrophy is being recognized with increasing frequency, it is imperative to have a better understanding of their broad etiologic diversity and their subtle differences

Leukoencephalopathies are disorders that selectively involve the white matter of the brain. Acquired causes of leukoencephalopathy include inflammatory, infectious, vascular, neoplastic, and toxic disorders. Hereditary leukoencephalopathies encompass conditions characterized by progressive destruction or loss of previously acquired central myelin (leukodystrophies) and conditions associated with impaired formation of myelin (dysmyelination or hypomyelination). The study of clinical features, neuroimaging patterns, and biochemical and neuropathologic features of leukoencephalopathies has led to the discovery of the genetic defects responsible for many of these conditions. Variations in phenotype-genotype correlation can make prediction of the underlying condition challenging. Despite recent advances in molecular studies, approximately 50% of patients with hereditary leukoencephalopathies remain without a diagnosis. A systematic approach to guide investigations is important for a diagnosis.

Context: Pelizaeus-Merzbacher Disease (PMD) is a rare X-linked recessive hypomyelinating leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene, associated with myelin sheath development and stability. The result is a broad spectrum of clinical phenotypes. Diagnosis is confirmed by genetic testing. Clinical features include hypotonia followed by progressive spasticity, nystagmus, ataxia and cognitive impairment. Males are more affected. Females are asymptomatic or present milder symptoms. Most cases arise from duplications, point and null mutations. Null mutations are associated with milder phenotypes. Brain Magnetic Resonance Imaging (MRI) may reveal hypomyelination. There is no disease modifying treatment for PMD. We aim to present the case of a woman with a novel variant of the PLP1 gene. Case report: A 38-year-old female presented with 23 years of progression of upper limb tremor, speech impairment, lower limb rigidity and urinary incontinence. She reported abnormal development of reading and writing skills. She had a brother with cognitive impairment, delayed motor development, gait disorder and generalized tonic-clonic seizures; and a sister with upper limb tremor, dysarthria and behavioral disorder. Hypomyelination was detected on brain MRI. Complete exome sequencing detected a novel likely pathogenic variant of PLP1 gene: ChrX(GRCh37):NC_000023.10:g.103041651del:NM _000533.3:c449del, p.Asp150AlafsTer10, heterozygous. Conclusions: The patient’s case resembles a milder form of PMD. This is supported by literature linking deletions and female sex to milder phenotypes. In 20 to 40% of cases with suggestive clinical findings, no PLP1 mutation is found. New studies are needed to identify other variants associated with PMD.