Leukodystrophy, Hypomyelinating, 5

A number sign (#) is used with this entry because of evidence that hypomyelinating leukodystrophy-5 (HLD5), also known as hypomyelination and congenital cataract (HCC), is caused by homozygous mutation in the FAM126A gene (610531) on chromosome 7p15.

For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080.

Clinical Features

Zara et al. (2006) identified 10 individuals from 5 families with a disorder characterized by congenital cataract, progressive neurologic impairment, and diffuse myelin deficiency as shown by brain magnetic resonance imaging (MRI). All individuals presented with bilateral cataract at birth or in the first 2 months of life and underwent ocular surgery. Initial psychomotor development was normal. At the end of the first year of life, development was delayed in all individuals. All achieved the ability to walk only with support. The individuals experienced slowly progressive pyramidal and cerebellar dysfunction, muscle weakness and wasting prevailingly in the lower limbs, and most became wheelchair-bound. Mental deficiency ranged from mild to moderate. Brain MRI showed abnormalities consistent with diffuse cerebral hypomyelination, whereas the cortex and deep gray matter structures were preserved. Neurophysiologic studies demonstrated peripheral neuropathy in 9 of the 10 individuals. Motor nerve conduction velocity was slightly to markedly slowed depending on the age of individuals, and the amplitude of compound muscle action potentials was also reduced. A sural nerve biopsy, performed in 4 individuals, showed deficiency of the myelin sheath in several nerve fibers and mild axonal loss, without active axonal degeneration. Zara et al. (2006) termed this novel constellation of clinical, neuroradiologic, neurophysiologic, and neuropathologic findings hypomyelination and congenital cataract (HCC).

Biancheri et al. (2007) presented further details on the HCC phenotype of the patients reported by Zara et al. (2006). Neurologic examination showed dysarthria, truncal hypotonia, brisk tendon reflexes, and extensor plantar responses. Cerebellar signs, such as intention tremor and truncal titubation, were also present. Mental retardation ranged from mild to moderate. Three patients had seizures. Neuroimaging showed progressive cerebral white matter atrophy and blurring of the gray matter/white matter interface at the cerebellar level in 6 patients.

Ugur and Tolun (2008) reported a large consanguineous Turkish family in which 5 individuals had hypomyelination and congenital cataracts associated with an intragenic deletion in the FAM126A gene (610531.0004). Clinical details of the 10-year-old male proband included congenital bilateral cataract, psychomotor regression beginning around 1 year of age, moderate mental retardation, and white matter changes in supratentorial structures and paraventricular regions. He also had a sensorimotor peripheral demyelinating neuropathy and never achieved walking. Two other affected individuals died at ages 2 and 12 years, respectively. One of the patients developed cataracts at age 9 years, suggesting clinical variability.

Biancheri et al. (2011) reported 9 patients from 7 families of Mediterranean origin with genetically confirmed HLD5. All patients had a normal perinatal period except 1, who had hypotonia and feeding difficulties. Five patients had bilateral cataracts at birth, 3 developed cataracts in the first months of life, and 1 had mild opacities at age 3 years. Developmental delay was noted at the end of the first year of life, with delayed standing and walking. Patients gradually lost the ability to walk and became wheelchair-bound between ages 3 and 15 years. Neurologic signs included truncal hypotonia, pyramidal signs, and muscle weakness and wasting of the lower limbs associated with a peripheral motor neuropathy. Three patients had cerebellar signs. Mild mental retardation was present in all patients; only 1 had a few seizures. Brain MRI was consistent with hypomyelination. There were also periventricular abnormalities with an anterior-to-posterior gradient of severity. Biancheri et al. (2011) concluded that the clinical variability of HLD5 is broader than previously described and that some patients may have a somewhat milder disease course, with onset of cataracts in infancy and some ability to walk in childhood.

Inheritance

The transmission pattern of HLD5 in the families reported by Biancheri et al. (2011) was consistent with autosomal recessive inheritance.

Mapping

By a genomewide scan in 3 consanguineous families, Zara et al. (2006) identified a unique segment of homozygosity on 7p21.3-p15.3 between markers D7S517 and D7S510. Parametric linkage analysis showed a cumulative maximum lod score of 4.53.

Molecular Genetics

Zara et al. (2006) systematically screened all 31 transcripts within the critical linkage region and identified 3 mutations in the FAM126A gene in 5 families. Two mutations affected splice sites (610531.0001 and 610531.0002), whereas the third was a missense mutation (610531.0003). The patient with the missense mutation, in whom a residual amount of protein was present, was still walking with support at age 20 years and did not have peripheral neuropathy, suggesting a correlation between reduced protein level and phenotypic severity. The findings of Zara et al. (2006) indicated that hyccin is essential for proper myelination in both the central and peripheral nervous system, and that there exists a molecular link between cerebral and peripheral myelination disorders and congenital cataract.