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Background Biallelic pathogenic variants in AIMP1 gene cause hypomyelinating leukodystrophy type 3, a severe neurodegenerative disorder with early onset characterized by microcephaly, axial hypotonia, epilepsy, spasticity, and developmental delay. Methods Clinical exome sequence was performed on patient's DNA and Sanger sequencing was used to confirm the candidate variant. To better characterize the effect of the genetic variant, functional analysis based on Sanger sequencing of the proband's complementary DNA (cDNA) was performed. Results We report a case of 2-year-old girl with microcephaly, significant global developmental delay, refractory epilepsy, flaccid paralysis, hypomyelination, leukodystrophy, and cerebral atrophy on brain magnetic resonance imaging (MRI). Clinical exome sequencing revealed a novel splice site variant c.603 + 1G > A in homozygosity in the AIMP1 gene. Studies on patient's cDNA showed that the variant disrupts the canonical donor splice site of intron 5, with the recognition of a cryptic splice site within exon 5, leading to the skipping of the last 24 nucleotides of this exon together with the flanking intron. This alteration is predicted to cause an in-frame deletion of eight amino acids (p.Val194_Gln201del) belonging to the tRNA-biding domain of the protein. Conclusion To the best of our knowledge, this is the first report of a splice site variant in the AIMP1 gene causing hypomyelinating leukodystrophy. The description of this patient not only expands the mutational spectrum of AIMP1 but also provides deeper insights on genotype–phenotype correlation by comparing the clinical features of our patient with previously reported affected individuals. [ABSTRACT FROM AUTHOR]

The enzyme ubiquitin-like modifier activating enzyme 5 (UBA5) plays an important role in activating ubiquitin-fold modifier 1 (UFM1) and its associated cascade. UFM1 is widely expressed and known to facilitate the post-translational modification of proteins. Variants in UBA5 and UFM1 are involved in neurodevelopmental disorders with early-onset epileptic encephalopathy as a frequently seen disease manifestation. Using whole exome sequencing, we detected a homozygous UBA5 variant (c.895C > T p. [Pro299Ser]) in a patient with severe global developmental delay and epilepsy, the latter from the age of 4 years. Magnetic resonance imaging showed hypomyelination with atrophy and T2 hyperintensity of the thalamus. Histology of the sural nerve showed axonal neuropathy with decreased myelin. Functional analyses confirmed the effect of the Pro299Ser variant on UBA5 protein function, showing 58% residual protein activity. Our findings indicate that the epilepsy currently associated with UBA5 variants may present later in life than previously thought, and that radiological signs include hypomyelination and thalamic involvement. The data also reinforce recently reported associations between UBA5 variants and peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Hypomyelination and congenital cataract (HCC) is characterized by congenital cataract, progressive neurologic impairment, and diffuse myelin deficiency. This autosomal recessive disorder is caused by homozygous variant in the FAM126A gene. Five consanguineous Tunisian patients, belonging to three unrelated families, underwent routine blood tests, electroneuromyography, and magnetic resonance imaging of the brain. The direct sequencing of FAM126A exons was performed for the patients and their relatives. We summarized the 30 previously published HCC cases. All of our patients were carriers of a previously reported c.414 + 1G > T (IVS5 + 1G > T) variant, but the clinical spectrum was variable. Despite the absence of a phenotype–genotype correlation in HCC disease, screening of this splice site variant should be performed in family members at risk. [ABSTRACT FROM AUTHOR]

Leukodystrophies are heterogeneous group of genetic white matter disorders with a wide range of neurologic and systemic manifestations. Defects in genes encoding aminoacyl tRNA (transfer ribonucleic acid) synthetase enzymes (aaRSs) are recently identified as the etiology of some leukodystrophies. Herein, we described two unrelated children referred to Children's Medical Center, Tehran, Iran, with developmental delay, nystagmus, seizures, psuedo-bulbar palsy and dystonia. Whole exome sequencing (WES) in both patients identified a homozygous (c.2T > C) variant in exon one of RARS gene, encoding cytoplasmic arginyl-tRNA synthetase. Our finding was confirmed by segregation analysis. In silico analyses of the c.2T > C variant showed its possible pathogenic role due to the absence of the start codon. Severe hypomyelination was the common neuroimaging finding of both cases. Spinal cord involvement was found in one of our patients which was not previously reported in studies. We, therefore, showed that RARS -related hypomyelination might affect spinal cord. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective This study aims to ascertain frequency of mutations in POLR3A or POLR3B, which are associated with 4H leukodystrophy, in a cohort of patients with unclassified hypomyelination. Methods and Results In a cohort of 22 patients with the magnetic resonance imaging (MRI) diagnosis of unclassified hypomyelination and without typical clinical signs, we evaluated clinical and MRI features. Developmental delay or intellectual disability, ataxia, and spasticity were frequent symptoms. POLR3A and POLR3B were sequenced. A compound heterozygote mutation in POLR3B was found in only one patient. Additional investigations allowed a definitive diagnosis in 10 patients. Conclusion Mutations in POLR3A or POLR3B are rare in patients with unclassified hypomyelination, and alternative diagnoses should be considered first. [ABSTRACT FROM AUTHOR]

A novel leukoencephalopathy, termed hypomyelinating leukoencephalopathy affecting early myelinating structures (HEMS), was recently described. Here we report on two patients affected by HEMS with a clinical picture characterized by early-onset nystagmus and thereafter progressive cerebellar signs and mild spasticity predominantly affecting the legs. In one patient, who has the longest follow-up described to date, we detected a mild worsening of the clinical and neuroradiologic picture after a long period of stability lasting until age 6 years. The most recent magnetic resonance image, performed at the age of 11 years, showed a more severe neuroradiologic picture characterized by involvement of almost the entire supratentorial white matter, with relative sparing of the subcortical fibers. We also provide spectroscopy results, not previously reported in this disorder, that support the idea of a progressive disease course on neuroimaging. Our findings suggest that HEMS patients should undergo a new magnetic resonance imaging evaluation after a certain interval to look for possible progression of the abnormalities. [ABSTRACT FROM AUTHOR]

CSF N-acetylaspartylglutamate (NAAG) has been found to be elevated in some hypomyelinating disorders. This study addressed the question whether it could be used as a marker for hypomyelination and as a means to distinguish between hypomyelinating disorders biochemically. We have measured CSF NAAG in a cohort of 28 patients with hypomyelination with known and unknown aetiology. NMG was found to be elevated in 7 patients, but was normal in the majority, including patients with defined hypomyelinating disorders. CSF NAAG is not a universal marker of hypomyelination, and the mechanism of its elevation remains poorly understood. [ABSTRACT FROM AUTHOR]

Fucosidosis is a rare autosomal recessive lysosomal storage disease, resulting from a deficiency of alpha-L-fucosidase. We report on the clinical and MRI findings of a girl with this disorder. Developmental delay became obvious at an age between 6 and 12 months. Cranial MRI at 16 months revealed severe global hypomyelination of both supra- and infratentorial white matter but no involvement of basal ganglia or thalamus. No clinical signs typical for fucosidosis were present at this time, and psychomotor development still progressed slowly. Since the age of 2 years, progressive neurological deterioration occurred. The diagnosis was established by severely decreased activity of alpha-L-fucosidase in plasma and leukocytes and confirmed by the detection of compound heterozygosity for two missense mutations of the FUCA1 gene. A follow-up imaging at the age of 4 years showed progression of neuroradiological abnormalities, particularly progressive involvement of basal ganglia and thalami. The course of this patient and her MRI findings enlarge the clinical and neuroradiological spectrum of fucosidosis. [ABSTRACT FROM AUTHOR]

We present four children, three of them boys, affected with an identical clinical pattern consisting of early-onset ataxia, delayed dentition, hypomyelination and cerebellar atrophy. Dental radiographs showed variable absence of succedaneous teeth. Proton MR spectroscopy in one child showed elevated white matter myoinositol. As the clinical and radiological picture in these patients is identical to that of four cases described earlier, we suggest that this disorder with ataxia, delayed dentition and hypomyelination (ADDH) represents a new entity. With the characteristic tooth abnormalities it should be straightforward to identify new patients in order to facilitate the search for the underlying genetic defect. [ABSTRACT FROM AUTHOR]

In recent years, several new white matter diseases have been identified based on magnetic resonance imaging and clinical findings. Formost newly defined disorders the genetic basis has been identified. However, there is still a large group of patients without a specific diagnosis. Hypomyelinating leukodystrophies are the largest group among them. In some disorders characterized by hypomyelination only central nervous system involvement is observed, but in some disorders involvement of other organs is observed as well, such as eyes or teeth. Pelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive hypomyelinating disorder of the central nervous system characterized by nystagmus, ataxia, and progressive spasticity. The disease is caused by mutations in GJC2, the gene that encodes the gap junction protein connexin 47. Here we describe hypomyelination and Müllerian agenesis syndrome in a girl who is homozygous for a novel mutation in the GJC2 gene. It is an open question whether this is an association by chance or a feature of PMLD not previously noted. [ABSTRACT FROM AUTHOR]

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