Huppke-Brendel Syndrome

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.

Suggestive Findings

HBS should be suspected in individuals with the following clinical, radiographic, electrophysiologic, and laboratory findings.

Clinical findings

• Bilateral congenital cataract
• Nystagmus
• Sensorineural hearing loss
• Severe developmental delay / intellectual disability
• Hypotonia
• Seizures, hypopigmented hair, and hypogenitalism (reported infrequently)

Radiographic findings on brain MRI examination

• Cerebellar hypoplasia
• Hypomyelination
• Wide subarachnoid spaces

Electrophysiologic findings. Brain stem auditory evoked potentials show absent wave forms.

Laboratory findings

• Low serum copper (usually 10%-20% of normal for age)
• Low serum ceruloplasmin (undetectable or very low)

Note: Identification of low serum copper and ceruloplasmin levels may be problematic in infants younger than age six months given the normally low serum concentration in all children at this age.

Establishing the Diagnosis

The diagnosis of HBS is established in a proband with the above Suggestive Findings and identification of biallelic pathogenic variants in SLC33A1 by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of HBS is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of HBS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Huppke-Brendel syndrome (HBS) is characterized by cataract, sensorineural deafness, and severe developmental delay in all reported individuals. To date, six individuals with HBS have been reported in the literature [Horváth et al 2005, Huppke et al 2012, Chiplunkar et al 2016].

Ocular features. Bilateral congenital cataracts were reported in all affected individuals. Affected individuals presented with poor visual fixation and rotary nystagmus. Two individuals underwent cataract extraction in early infancy; there was improvement in visual fixation and nystagmus in one child [Horváth et al 2005] and no improvement in vision in the other [Chiplunkar et al 2016].

Sensorineural hearing loss manifests during infancy. Brain stem auditory evoked potentials in two individuals showed absent waveforms. Otoacoustic emissions were absent bilaterally in one individual.

Neurologic features. Axial hypotonia was present in all infants. Motor delay was apparent in the first few months of life in all reported individuals. Lack of head control and paucity of movements in the limbs were evident. None of the individuals reported to date were able to sit or walk independently. None learned to speak. Developmental progress has been reported only in one individual who received copper histidinate therapy from age five months [Horváth et al 2005]. Follow up at age 13 months in this individual showed good head control, rolling over, reaching out for objects, and improved alertness and communication.

Deep tendon reflexes were normal and symmetric.

Two of the six reported individuals had seizures.

Orthopedic complications. Affected individuals are at increased risk for scoliosis and joint contractures [Author, personal communication].

Other. Hypopigmented hair and hypogenitalism were reported in one individual [Chiplunkar et al 2016]. This child had micropenis with bilaterally descended testes. The hair was uniformly hypopigmented and sparse. Hair analysis under polarized light microscopy showed uniform and finely granulated melanin pigment and no clumps. There was no kinking or abnormal polarization.

Prognosis. All affected individuals died between age ten months and six years. Causes of death included pneumonia, renal failure, and multiorgan failure. The cause of multiorgan failure was not reported.

Neuroimaging. Brain MRI showed hypomyelination, cerebellar hypoplasia mainly affecting the vermis, hypoplasia of the temporal lobes, and wide subarachnoid spaces (see Figure 1) [Horváth et al 2005, Huppke et al 2012, Chiplunkar et al 2016].

Figure 1.

Brain MRI in a child with HBS at age four months A, B. T₁-weighted axial view (A) and T₂-weighted axial view (B) show presence of myelin only in the posterior limb of the internal capsule, indicating delayed myelination. Widened subarachnoid spaces are (more...)

Histopathology on muscle biopsy

• Subsarcolemmal proliferation and vacuolization in few type 1 fibers are reported. No typical ragged red fibers or ragged blue fibers or COX-negative fibers are seen [Horváth et al 2005, Chiplunkar et al 2016].
• Biochemical measurements of the respiratory chain enzymes showed significantly reduced activity of COX with 30% residual activity in one individual [Horváth et al 2005] and 35% residual activity in another [Chiplunkar et al 2016].

Genotype-Phenotype Correlations

The number of individuals with confirmed pathogenic variants in SLC33A1 is too small to make any conclusive genotype-phenotype correlations.

Nomenclature

HBS may also be referred to as congenital cataracts, hearing loss, and neurodegeneration (CCHLND).

Prevalence

Prevalence of HBS is unknown. Only six affected individuals have been reported to date.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Huppke-Brendel syndrome (HBS), the following evaluations are recommended if they have not already been completed:

• Ophthalmologic evaluation
• Assessment of feeding and nutrition
• Developmental assessment
• Audiologic evaluation including brain stem auditory evoked response and otoacoustic emissions testing
• Complete neurologic assessment
• Electroencephalography if seizures are suspected
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

The following are indicated:

• Cataract extraction 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

Individuals with HBS require the following periodically:

• Developmental and neurologic assessment
• Nutritional and growth evaluation
• Hearing evaluation
• Ophthalmologic evaluation
• Orthopedic evaluation because of increased risk for scoliosis and contractures

Evaluation of Relatives at Risk

It is appropriate to evaluate infants at risk for HBS in order to identify as early as possible those who would benefit from prompt removal of cataracts as well as feeding and developmental support. Evaluations can include the following:

• Clinical exam, ophthalmologic exam for cataracts, and audiologic evaluation in an at-risk newborn prior to molecular testing or while waiting for molecular results
  Note: Serum copper and ceruloplasmin levels may not be informative in a newborn because serum ceruloplasmin and, to a lesser degree, serum copper are very low in normal neonates (even more so in premature infants); further, the depletion of copper stores may not be noticeable in the first few months of life even in patients with known disorders of copper transport.
• Molecular genetic testing if the pathogenic variants in the family are known

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Treatment with copper histidinate in three affected individuals did not result in an increase in serum copper or ceruloplasmin. Clinical improvement was reported in one individual, who died at age four years.

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