Clinical characteristics.

Huppke-Brendel syndrome (HBS) is characterized by bilateral congenital cataracts, sensorineural hearing loss, and severe developmental delay. To date, 11 individuals (ten children and one adult) with HBS have been reported in the literature. All children presented in infancy with axial hypotonia; motor delay was apparent in the first few months of life with a 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 could sit or walk independently. All affected children died between age ten months and six years. The only adult reported to date had a history of developmental delay, moderately impaired intellectual development, partial hearing loss from childhood, spastic ataxia, hypotonia, and unilateral tremor of parkinsonian type. Low serum copper and ceruloplasmin levels and increased urinary copper levels were reported. Brain MRI showed global atrophy including cerebellar atrophy.

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 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; physical therapy 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.

Evaluation of relatives at risk: It is appropriate to evaluate at-risk newborn sibs 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.

Genetic counseling.

HBS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SLC33A1 pathogenic variant, each sib of an affected individual has at conception 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 and prenatal/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 cataracts
• Nystagmus
• Sensorineural hearing loss
• Severe developmental delay / intellectual disability and regression of acquired milestones
• Hypotonia
• Seizures
• Poor weight gain and growth deficiency

Radiographic findings (on brain MRI examination)

• Cerebellar hypoplasia / cerebellar atrophy
• Cerebral atrophy
• Hypomyelination/dysmyelination
• White matter volume loss
• Wide subarachnoid spaces
• Posterior cranial fossa cyst

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 suggestive findings and biallelic pathogenic (or likely pathogenic) variants in SLC33A1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic SLC33A1 variants of uncertain significance (or of one known SLC33A1 pathogenic variant and one SLC33A1 variant of uncertain significance) does not establish or rule out the diagnosis.

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). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Huppke-Brendel syndrome (HBS) is characterized by congenital cataracts, sensorineural hearing loss, and severe developmental delay in all reported children. One adult presented with less severe features. To date, 11 individuals (ten children and one adult) with HBS have been reported in the literature [Horváth et al 2005, Huppke et al 2012, Chiplunkar et al 2016, Monastiri et al 2021, Kirk et al 2022, Šikić et al 2022, Šikić et al 2024].

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. To date, all individuals have required feeding support. None of the affected children reported to date were able to sit or walk independently. None learned to speak. Developmental progress has been reported only in one child 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. Copper histidinate therapy was also tried in another affected individual [Šikić et al 2022]; there was no clinical improvement noted after six months of treatment, although there was an increase in serum copper and ceruloplasmin.

Two reported children had seizures. Burst suppression pattern has been described in the EEG of one individual [Šikić et al 2022].

Dyskinetic movements of the head, trunk, and limbs were noted in one affected individual at age 14 months [Šikić et al 2024].

Deep tendon reflexes were normal and symmetric.

Poor weight gain is common in children with HBS. Onset is postnatal and could be attributed to feeding difficulty.

Orthopedic complications. Affected individuals are at increased risk for scoliosis and joint contractures [Authors, personal observations]. Pathologic fracture has been reported in one individual. Serum alkaline phosphatase, 25-hydroxyvitamin D₃, calcium, and phosphate in this individual were normal, and lumbar bone density scan showed severe osteopenia with a z score of −9.0 [Šikić et al 2022]. Hypermobile joints have also been reported [Šikić et al 2022, Šikić et al 2024].

Dysmorphic facial features have been reported in some individuals, including hypotelorism, short palpebral fissures, depressed nasal bridge, thin vermilion of the upper lip, cleft soft palate, micrognathia, and low-set ears [Šikić et al 2022, Šikić et al 2024].

Other

• Secondary hypothyroidism (1 individual) [Šikić et al 2024]
• Micropenis with bilaterally descended testes and hypopigmented hair (1 individual) [Chiplunkar et al 2016]. 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.

Later onset. To date, only one adult has been reported who presented with a milder form of HBS with a history of developmental delay, moderately impaired intellectual development, partial hearing loss from childhood, spastic ataxia, hypotonia, and unilateral tremor of parkinsonian type [Kirk et al 2022]. At age 53 years, deterioration in neurologic status occurred, including dysphagia, dysarthria, and loss of mobility, which were attributed to medication side effects. Brain MRI showed global atrophy including cerebellar atrophy.

Prognosis. All affected individuals died between age ten months and six years, with one exception of an adult who survived until age 53 years. Causes of death included pneumonia, kidney failure, and multiorgan failure. The cause of multiorgan failure was not reported.

Neuroimaging. Brain MRI showed hypomyelination, cerebellar hypoplasia mainly affecting the vermis, Dandy-Walker malformation, hypoplasia of the temporal lobes, wide subarachnoid spaces (see Figure 1), bilateral frontal subdural hygromas, and megacisterna magna [Horváth et al 2005, Huppke et al 2012, Chiplunkar et al 2016, Šikić at al 2022, Šikić et al 2024]. On brain magnetic resonance spectroscopy (MRS), a normal metabolite ratio was obtained using the chemical shift imaging (CSI) technique [Šikić et al 2022].

Figure 1.

Brain MRI in a child with Huppke-Brendel syndrome 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 (more...)

Cerebrospinal fluid (CSF) studies. Decreased levels of many N-acetylated amino acids in CSF and some in plasma of an individual with HBS have been described. Decreased levels of N-acetylated amino acids in CSF are noted to be a metabolic fingerprint in HBS and a potential biomarker [Šikić et al 2022].

Histopathology on muscle biopsy

• Subsarcolemmal proliferation and vacuolization in few type 1 fibers are reported. No typical ragged red fibers, 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 11 affected individuals (ten children and one adult) have been reported to date.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with HBS, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for HBS. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Evaluation of Relatives at Risk

It is appropriate to evaluate at-risk newborn sibs 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;
• Molecular genetic testing for the SLC33A1 pathogenic variants identified in the proband.

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 individuals with known disorders of copper transport.

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.

Therapeutic trials with acetylation therapy, consisting of N-acetyl cysteine and ketogenic diet, did not normalize the concentration of N-acetylated amino acids in cerebrospinal fluid or plasma and no clinical improvement was noted.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Huppke-Brendel syndrome (HBS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an SLC33A1 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an SLC33A1 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an SLC33A1 pathogenic variant, each sib of an affected individual has at conception 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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with HBS are not known to reproduce [Kirk et al 2022].

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an SLC33A1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the SLC33A1 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk sibs for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the SLC33A1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

SLC33A1 encodes acetyl-coenzyme A transporter 1 (AT-1). AT-1 is an endoplasmic reticulum (ER) membrane transporter that regulates the influx of acetyl-CoA into the ER lumen [Jonas et al 2010], a key step for the intraluminal acetylation of ER resident and transiting proteins. This is essential for the induction of tightly controlled autophagy-dependent ER-associated degradation (ERAD-II), which allows the cell to recover from the resulting transient accumulation of protein aggregates [Pehar et al 2012].

SLC33A1 pathogenic variants cause severe loss of protein function. The functional consequences have been studied in a number of pathogenic variants. The p.Ala110Pro pathogenic variant results in abnormal function of the first and second transmembrane domain [Huppke et al 2012].

The relationship between AT-1 and low serum copper and ceruloplasmin levels is unclear at present. One theory is that ceruloplasmin, which is a glycoprotein, requires AT-1-dependent transient acetylation for proper function. Studies in HepG2 cells with reduced AT-1 expression demonstrated 30% less ceruloplasmin excretion consistent with AT-1 deficiency causing reduced ceruloplasmin levels [Huppke et al 2012]. Individuals with HBS display no signs of copper toxicity, as occurs in individuals with Wilson disease with hepatic cirrhosis. Copper analysis in tissues in a few affected individuals did not reveal any abnormality.

Mechanism of disease causation. Loss of function

Revision History

• 3 April 2025 (sw) Comprehensive update posted live
• 13 June 2019 (sw) Review posted live
• 10 May 2018 (bps) Original submission

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