Objective: To define the clinical, neurophysiological, neuroimaging and pathological findings from a patient carrying a FAM126A homozygous exon 3-7 deletion.

Background: Hypomyelinating leukodystrophies constitute a heterogeneous group of genetically determined white matter disorders defined by an abnormal development of the CNS and peripheral myelin, with characteristic patterns in brain MRI and a wide spectrum of clinical features and severity. HCC, also known as HLD5, is a rare inherited condition caused by the deficiency of the membrane protein hyccin, encoded by the FAM126A gene, with a broad clinical range characterized by congenital cataracts and progressive neurological impairment.

Method: A 38-year-old male from the Punjab area (Pakistan) with familial history of consanguinity, presented developmental delay, and congenital cataracts. He was able to stand but at age 28 he showed a progressive gait impairment, optic ataxia, flaccid paraparesis, bilateral cerebellar syndrome and a progressive generalized muscular atrophy with kyphoscoliosis.  Electromyogram, electroencephalogram, brain magnetic resonance imaging, sural nerve biopsy and genetic panel were performed. The coding region of the FAM126A gene was analyzed by PCR amplification and electrophoresis.

Results: The magnetic resonance showed a diffusely abnormal white matter with hyperintensity on T2-weighted sequences affecting also brainstem and basal ganglia and severe subcortical atrophy.  Blood tests revealed slightly elevated creatine kinase with normal levels of long fatty acid chains. The electroencephalogram showed a slow pattern, and the electromyogram was congruent with a severe demyelinating sensitive and motor polyneuropathy. Sural nerve biopsy was compatible with a small fiber axonal loss and demyelination of neural fibers. Analysis of the FAM126A gene coding region showed a homozygous deletion of exons 3-7.

Interpretation: We report the first case of a gene rearrangement (a large deletion in the FAM126A gene) as the cause of hereditary HLD5, that it is associated with severe hypomyelination of the central and peripherical nervous system.

Conclusion: We report the first case of a gene rearrangement (a large deletion in the FAM126A gene) as the cause of hereditary HLD5, that it is associated with severe hypomyelination of the central and peripherical nervous system.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gene-rearrangement-as-the-cause-of-hereditary-hypomyelinating-leukodyistrophy-disease-type-5-hld5/