Clinical characteristics: Huppke-Brendel syndrome (HBS) is characterized by bilateral congenital cataracts, sensorineural hearing loss, and severe developmental delay. To date, six individuals with HBS have been reported in the literature. All presented in infancy with axial hypotonia; motor delay was apparent in the first few months of life with lack of head control and paucity of limb movement. Seizures have been reported infrequently. In all individuals described to date serum copper and ceruloplasmin levels were very low or undetectable. Brain MRI examination showed hypomyelination, cerebellar hypoplasia mainly affecting the vermis, and wide subarachnoid spaces. None of the individuals reported to date were able to sit or walk independently. All affected individuals died between age ten months and six years.
Diagnosis/testing: The diagnosis of HBS is established in a proband with characteristic features (bilateral congenital cataracts, sensorineural hearing loss, severe developmental delay, very low serum copper and ceruloplasmin levels) and biallelic (compound heterozygous or homozygous) pathogenic variants in SLC33A1 identified by molecular genetic testing.
Management: Treatment of manifestations: Cataract extraction is indicated in the first few months of life; early feeding tube placement to manage difficulties with swallowing, ensure adequate nutrition, and reduce the risk of aspiration; developmental intervention; physiotherapy to maintain muscle function and prevent contractures.
Surveillance: Periodic developmental and neurologic assessment; nutritional and growth evaluation; hearing evaluation; ophthalmologic evaluation; orthopedic evaluation for increased risk of scoliosis and contractures.
Genetic counseling: HBS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SLC33A1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
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