Hypomyelination and Congenital Cataract: Neuroimaging Features of a Novel Inherited White Matter Disorder

Rossi, Andrea; Biancheri, Roberta; Zara, Federico; Bruno, Claudio; Uziel, Graziella; Knaap, Marjo S. van der; Minetti, Carlo; Tortori-Donati, Paolo

doi:10.3174/ajnr.a0792

Cited by 26 publications

(23 citation statements)

References 10 publications

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“…The association of congenital cataract and neurological disease is seen in many syndromes, such as Marinesco–Sjögren syndrome , Warburg Micro syndrome , hypomyelination and congenital cataract syndrome . A comparison between these syndromes and the syndrome described in this report is provided in Table .…”

Section: Discussionmentioning

confidence: 94%

A novel syndrome of abnormal striatum and congenital cataract: evidence for linkage to chromosomes 11

Al‐Owain

Al-Zahrani²,

Al-Bakheet³

et al. 2012

Clinical Genetics

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We report a consanguineous family of three girls and one boy affected with a novel syndrome involving the lens and the basal ganglia. The phenotype is strikingly similar between affected siblings with cognitive impairment, attention deficit hyperactivity disorder (ADHD), microcephaly, growth retardation, congenital cataract, and dystonia. The magnetic resonance imaging showed unusual pattern of swelling of the caudate heads and thinning of the putamina with severe degree of hypometabolism on the [18F] deoxyglucose positron emission tomography. Furthermore, the clinical assessment provides the evidence that the neurological phenotype is very slowly progressive. We utilized the 10K single-nucleotide polymorphism (SNP) microarray genotyping for linkage analysis. Genome-wide scan indicated a 45.9-Mb region with a 4.2353 logarithm of the odds score on chromosome 11. Affymetrix genome-wide human SNP array 6.0 assay did not show any gross chromosomal abnormality. Targeted sequencing of two candidate genes within the linkage interval (PAX6 and B3GALTL) as well as mtDNA genome sequencing did not reveal any putative mutations.

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Section: Discussionmentioning

confidence: 94%

A novel syndrome of abnormal striatum and congenital cataract: evidence for linkage to chromosomes 11

Al‐Owain

Al-Zahrani²,

Al-Bakheet³

et al. 2012

Clinical Genetics

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“…In these cases, some with white matter changes have shown increased myo-inositol/creatine (Cr) and decreased N-acetylaspartate/Cr, reflecting astrogliosis and neuroaxonal loss1718. Although broad lipid peaks have sometimes been detected in child food adrenoleukodystrophy and peroxisome disorders, emergence of clear, sharp lipid peaks have been reported in very limited diseases such as Sjögren-Larsson syndrome1920 hypomyelination and congenital cataract21, which show distinct clinical manifestations from SCA and SPGs. No SNVs were detected in the causative gene of Sjögren-Larsson syndrome ( ALDH3A2 ).…”

Section: Discussionmentioning

confidence: 99%

Late-onset spastic ataxia phenotype in a patient with a homozygous DDHD2 mutation

Doi

Ushiyama²,

Baba

et al. 2014

Sci Rep

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Autosomal recessive cerebellar ataxias and autosomal recessive hereditary spastic paraplegias (ARHSPs) are clinically and genetically heterogeneous neurological disorders. Herein we describe Japanese siblings with a midlife-onset, slowly progressive type of cerebellar ataxia and spastic paraplegia, without intellectual disability. Using whole exome sequencing, we identified a homozygous missense mutation in DDHD2, whose mutations were recently identified as the cause of early-onset ARHSP with intellectual disability. Brain MRI of the patient showed a thin corpus callosum. Cerebral proton magnetic resonance spectroscopy revealed an abnormal lipid peak in the basal ganglia, which has been reported as the hallmark of DDHD2-related ARHSP (SPG 54). The mutation caused a marked reduction of phospholipase A1 activity, supporting that this mutation is the cause of SPG54. Our cases indicate that the possibility of SPG54 should also be considered when patients show a combination of adult-onset spastic ataxia and a thin corpus callosum. Magnetic resonance spectroscopy may be helpful in the differential diagnosis of patients with spastic ataxia phenotype.

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“…Hypomyelination has been reported in association with several established disorders, including the prototype PMD, PMLD, Cockayne syndrome type B (CSB [MIM 133540]), hypomyelination, atrophy of the basal ganglia and cerebellum, and hypomyelination and congenital cataract syndrome (HCC [MIM 610532]), among others. 47 Analysis of mutations in PLP1 encoding the major protein of CNS myelin has revealed the previously unappreciated role of glial myelination in the maintenance of CNS integrity. There is a large overlap in the clinical and MRI features of MitCHAP-60, PMD, and PMLD, 48 suggesting that the HSPD1, PLP1, and GJA12 gene products, among others, may comprise components of a common pathway, whose disruption may lead to hypomyelination and SPG.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Hsp60 Chaperonopathy Causes an Autosomal-Recessive Neurodegenerative Disorder Linked to Brain Hypomyelination and Leukodystrophy

Magen

Georgopoulos

Bross

et al. 2008

The American Journal of Human Genetics

190

155

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Hypomyelinating leukodystrophies (HMLs) are disorders involving aberrant myelin formation. The prototype of primary HMLs is the X-linked Pelizaeus-Merzbacher disease (PMD) caused by mutations in PLP1. Recently, homozygous mutations in GJA12 encoding connexin 47 were found in patients with autosomal-recessive Pelizaeus-Merzbacher-like disease (PMLD). However, many patients of both genders with PMLD carry neither PLP1 nor GJA12 mutations. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD, in which linkage to PLP1 and GJA12 was excluded. Using homozygosity mapping and mutation analysis, we have identified a homozygous missense mutation (D29G) not previously described in HSPD1, encoding the mitochondrial heat-shock protein 60 (Hsp60) in all affected individuals. The D29G mutation completely segregates with the disease-associated phenotype. The pathogenic effect of D29G on Hsp60-chaperonin activity was verified by an in vivo E. coli complementation assay, which demonstrated compromised ability of the D29G-Hsp60 mutant protein to support E. coli survival, especially at high temperatures. The disorder, which we have termed MitCHAP-60 disease, can be distinguished from spastic paraplegia 13 (SPG13), another Hsp60-associated autosomal-dominant neurodegenerative disorder, by its autosomal-recessive inheritance pattern, as well as by its early-onset, profound cerebral involvement and lethality. Our findings suggest that Hsp60 defects can cause neurodegenerative pathologies of varying severity, not previously suspected on the basis of the SPG13 phenotype. These findings should help to clarify the important role of Hsp60 in myelinogenesis and neurodegeneration.

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Hypomyelination and Congenital Cataract: Neuroimaging Features of a Novel Inherited White Matter Disorder

Abstract: BACKGROUND AND PURPOSE:Hypomyelination and congenital cataract (HCC) is an autosomal recessive white matter disease caused by deficiency of hyccin, a membrane protein implicated in both central and peripheral myelination. We aimed to describe the neuroimaging features of this novel entity.

Cited by 26 publications

References 10 publications

A novel syndrome of abnormal striatum and congenital cataract: evidence for linkage to chromosomes 11

A novel syndrome of abnormal striatum and congenital cataract: evidence for linkage to chromosomes 11

Late-onset spastic ataxia phenotype in a patient with a homozygous DDHD2 mutation

Mitochondrial Hsp60 Chaperonopathy Causes an Autosomal-Recessive Neurodegenerative Disorder Linked to Brain Hypomyelination and Leukodystrophy

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