Congenital Cataracts, Hearing Loss, And Neurodegeneration

A number sign (#) is used with this entry because congenital cataracts, hearing loss, and neurodegeneration (CCHLND) is caused by homozygous or compound heterozygous mutation in the SLC33A1 gene (603690) on chromosome 3q25.

Description

Congenital cataracts, hearing loss, and neurodegeneration (CCHLND) is an autosomal recessive disorder characterized by congenital cataracts, severe psychomotor retardation, and hearing loss associated with decreased serum ceruloplasmin and copper. Brain MRI shows cerebral and cerebellar atrophy and hypomyelination (summary by Huppke et al., 2012).

Clinical Features

Horvath et al. (2005) reported a boy, born of consanguineous Arab parents, who presented in the first weeks of life with severe hypotonia, weakness of the neck muscles, and bilateral congenital cataracts. Examination at age 4 months showed delayed psychomotor development, severe hypotonia, inability to fix gaze, and rotary nystagmus. Laboratory studies showed low serum copper and ceruloplasmin, and neutropenia. Skeletal muscle biopsy showed some enlarged and abnormal mitochondria and decreased cytochrome c oxidase activity. Brain MRI at age 5 months revealed Dandy-Walker malformation, hypoplasia of the cerebellar vermis, and hypoplasia of the temporal lobes. Treatment with copper histidinate supplementation resulted in marked clinical improvement by ages 8 and 13 months: hypotonia was less severe, and there was complete restoration of cytochrome c oxidase activity in skeletal muscle, although serum copper levels did not increase significantly. At age 13 months, he was noted to have bilateral hearing impairment. Patient fibroblasts showed an increased copper uptake with normal retention. Immunoblot analysis excluded deficiencies of ATP7A (300011), which causes Menkes disease (309400), and ATP7B (606882), which causes Wilson disease (277900), 2 disorders of copper metabolism. Huppke et al. (2012) provided follow-up of the patient reported by Horvath et al. (2005), who died at age 4 years.

Huppke et al. (2012) reported 4 patients from 3 families with a phenotype similar to that reported in the patient by Horvath et al. (2005). All had severe psychomotor retardation, with inability to sit or walk independently and lack of speech, as well as congenital cataracts and hearing loss. Additional, more variable neurologic features included nystagmus (3) and seizures (2). Brain MRI showed cerebral and cerebellar atrophy, wide subarachnoid spaces, and hypomyelination. Serum copper was low (10 to 20% of normal), and ceruloplasmin was very low. All patients died between ages 22 months and 6 years, from various causes. Two patients treated with copper supplementation showed no clinical improvement. The patients did not show evidence of total body copper deficiency or copper toxicity.

Inheritance

The transmission pattern of congenital cataracts, hearing loss, and neurodegeneration in the families reported by Huppke et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

By linkage analysis followed by candidate gene sequencing in 3 consanguineous families with autosomal recessive congenital cataracts, hearing loss, and neurodegeneration associated with low serum copper and ceruloplasmin, Huppke et al. (2012) identified 5 different pathogenic mutations in the SLC33A1 gene in the homozygous or compound heterozygous state (603690.0002-603690.0006). Knockdown of SLC33A1 in hepatic cells caused a 30% reduction of ceruloplasmin secretion, indicating that SLC33A1 expression and ceruloplasmin secretion are connected. None of the parents who were heterozygous carriers showed signs of spastic paraplegia.

One of the patients reported by Huppke et al. (2012), who had a nonsense mutation (603690.0004), was a Turkish boy who had additional features not found in the other patients, including neonatal hypotonia, hypoglycemia, and a pericardial effusion. In this patient, Huppke et al. (2012) later identified a homozygous missense mutation in the CCS gene (603864.0001) and suggested that a defect in copper homeostasis or SOD1 deficiency may have contributed to the phenotype.