A number sign (#) is used with this entry because of evidence that Huppke-Brendel syndrome (HPBDS) is caused by homozygous or compound heterozygous mutation in the SLC33A1 gene (603690) on chromosome 3q25.

Huppke-Brendel syndrome (HPBDS) 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).

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.

Chiplunkar et al. (2016) reported a 7-month-old boy, born to first-cousin parents from India, with Huppke-Brendel syndrome. The patient had hypopigmented hair and bilateral congenital cataracts at birth. He underwent surgery for cataracts at 2 months of age. At 7 months of age, he was noted to have a full face with hypopigmented hair and skin and small male genitalia. His weight was at the 75th centile for age, while head circumference was less than the 3rd centile. He had nystagmus and significant developmental delay. Serum copper and ceruloplasmin levels were low. MRI of the brain showed hypomyelination and cerebellar hypoplasia. He died at age 10 months.

Monastiri et al. (2021) reported 2 brothers, born of consanguineous Tunisian parents, with Huppke-Brendel syndrome. The 1-year-old brother had cutis marmorata, recurrent pneumonia, neurologic regression, and seizures with onset at 7 months of age. Brain MRI showed cerebral atrophy, mega cisterna magna, and suspected Leigh syndrome. Serum copper was slightly elevated and plasma ceruloplasmin was low. He died at the age of 16 months. In the 5-month-old brother, mild hypotonia, horizontal nystagmus, and bilateral cataracts were noted. He had neurodevelopmental regression with recurrent aspiration pneumonia. Both serum copper and plasma ceruloplasmin were low. He was treated with enteral copper without improvement.

Sikic et al. (2022) reported a 3-year-old girl, born to nonconsanguineous Croatian parents, with Huppke-Brendel syndrome She had mild hypotonia and bilateral cataracts in the newborn period. At 5 months, deterioration in her development was noted, with improvement after 6 months of intensive therapies. Clinical deterioration was again noted at 14 months, when she was hospitalized due to meningitis and urosepsis. She was noted to have significant dyskinesia of the arms, head and trunk and uncoordinated eye movements. She had nystagmus. Joints were hypermobile, and facial features included hypotelorism, thin upper lip, and micrognathia. Recurrent seizures developed, leading to initiation of antiepileptic therapy. A brain MRI showed bilateral frontal subdural hygromas, cystic formation in the posterior cranial fossa, and diffuse hypomyelination and cerebellar hypoplasia. Bilateral hearing loss was identified. She had low serum copper and ceruloplasmin concentrations. Subcutaneous copper histidinate therapy was started at age 18 months with no clinical improvement, although an increase in serum copper and ceruloplasmin was noted. She was noted to have a distal femur fracture at age 3 years without preceding trauma. At her last evaluation at age 3 years and 4 months, she was microcephalic (head circumference less than 1st centile) and had pale skin and white sparse kinky hair. She had severe psychomotor disability: she was bedridden, somnolent with no visual contact, responded only to painful stimuli, was tube-fed, and used tracheostomy with noninvasive ventilation as breathing support. She continued to have daily seizures despite treatment with 3 antiepileptic medications, and an EEG shows burst suppression elements. Levels of ceruloplasmin and copper were low, despite continuous copper histidinate therapy. Although N-terminal protein acetylation and acetyl-CoA levels in fibroblasts appeared normal, the authors found decreased levels of many N-acetylated amino acids in the cerebrospinal fluid and suggested that these could be potential biomarkers for the condition. Sikic et al. (2022) also reviewed phenotype and genotype of previously reported patients with Huppke-Brendel syndrome.

Kirk et al. (2022) reported a 53-year-old Danish woman with a mild form of Huppke-Brendel syndrome who had previously been diagnosed with Wilson disease (277900) because of elevated urinary copper and low ceruloplasmin levels. The patient initially presented in childhood with developmental delay and partial hearing loss. At age 29 years, she had moderately impaired intellectual development, partial hearing loss, spastic ataxia, hypotonia, and a unilateral tremor of parkinsonian type. She had low serum ceruloplasmin and serum copper levels, and urinary excretion of copper was moderately elevated, and Wilson disease was diagnosed. Zinc therapy was initiated, and she remained stable, without progression of her neurologic symptoms. At 49 years of age, she developed severe dysphagia and experienced a loss of mobility and bladder and bowel control. Penicillamine was added and her antipsychotic and antiepileptic medications were adjusted, with improvement in her dysphagia and mobility. Brain MRI showed no changes consistent with Wilson disease but showed global atrophy including cerebellar atrophy. These findings, along with genetic analysis finding no variants in the ATP7B (606882) gene and identifying variants in the SLC33A1 gene, led to a diagnosis of Huppke-Brendel syndrome.

The transmission pattern of Huppke-Brendel syndrome in the families reported by Huppke et al. (2012) was consistent with autosomal recessive inheritance.

By linkage analysis followed by candidate gene sequencing in 3 consanguineous families with Huppke-Brendel syndrome, Huppke et al. (2012) identified 5 different pathogenic mutations in the SLC33A1 gene in 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.

By exome sequencing in a 7-month-old boy, born to first-cousin parents from India, with HPBDS, Chiplunkar et al. (2016) identified a homozygous 2-bp deletion in exon 1 of the SLC33A1 gene (c.542_543delTG; 603690.0008), predicted to result in a frameshift and premature truncation of the protein (Val181GlyfsTer6). The unaffected parents were heterozygous for the mutation.

In 2 brothers, born to consanguineous parents from Tunisia, with HPBDS, Monastiri et al. (2021) identified homozygosity for a splice site mutation in the SLC33A1 gene (c.1267-1G-A; 603864.0003). This mutation had been reported by Huppke et al. (2012) in Tunisian sibs, suggesting a founder effect in that population.

In a 3-year-old girl, born to nonconsanguineous Croatian parents, with HPBDS, Sikic et al. (2022) identified homozygosity for a nonsense mutation in the SLC33A1 gene (Y377X; 603690.0009). Both unaffected parents were heterozygous for the mutation.

By exome sequencing in a 53-year-old Danish woman with a mild form of HPBDS who had been diagnosed with Wilson disease (277900), Kirk et al. (2022) identified compound heterozygosity for variants in the SLC33A1 gene: a c.1331T-C transition, resulting in an ile444-to-thr (I444T) substitution, and a 3-bp deletion (c.817_819del), resulting in deletion of threonine at codon 273. The first variant was not found in gnomAD, whereas the second was found 3 times in heterozygous state only. Both affected amino acids were highly evolutionarily conserved. No clinical information on the deceased parents was available. Kirk et al. (2022) classified these variants as variants of uncertain significance based on ACMG criteria.