A number sign (#) is used with this entry because of evidence that MEDNIK syndrome (MEDNIK) is caused by homozygous mutation in the AP1S1 gene (603531) on chromosome 7q22.

Mutation in the AP1B1 gene (600157) causes a disorder with overlapping features (KIDAR; 242150).

MEDNIK syndrome is a severe multisystem disorder characterized by impaired intellectual development, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma (summary by Montpetit et al., 2008).

Patients with MEDNIK exhibit distinct dysmorphic features, including high forehead, upslanting palpebral fissures, depressed nasal bridge, and low-set ears, as well as growth retardation and moderate to severe intellectual disability, with brain atrophy on imaging. Other features include sensorineural deafness, enteropathy with congenital diarrhea, abnormalities of copper metabolism associated with liver disease, and ichthyosis, hyperkeratosis, and erythroderma. Peripheral neuropathy has also been observed in adult patients (Martinelli et al., 2013).

MEDNIK syndrome shows phenotypic similarities to CEDNIK syndrome (609528).

Erythrokeratodermia variabilis (EKV; 133200) is a congenital disorder of the skin that causes hyperkeratosis and red patches of variable sizes, shapes, and duration. In 5 children from 3 families originating from the Kamouraska region of the province of Quebec, Saba et al. (2005) described an atypical form of erythrokeratodermia variabilis, which they designated erythrokeratodermia variabilis-3 (Kamouraska type) and symbolized EKV3. This form was similar to a disorder previously described by Beare et al. (1972) and included sensorineural deafness, peripheral neuropathy, and psychomotor retardation; however, in addition to these symptoms, the Kamouraska patients had congenital diarrhea, an elevation of very long chain fatty acids (VLCFAs), and a recessive mode of inheritance. Two of the children died at an early age from severe congenital diarrhea.

Montpetit et al. (2008) restudied the patients reported by Saba et al. (2005) and identified another family from Quebec with the disorder. Features included high forehead with upslanting palpebral fissures, congenital sensorineural deafness, psychomotor retardation and mental retardation, peripheral neuropathy, hypotonia, and ichthyosiform erythroderma. Gastrointestinal problems included severe diarrhea, resulting in death in infancy in 4 patients, hepatic fibrosis, cirrhosis, and cholestasis. Two patients had cataracts.

Martinelli et al. (2013) evaluated copper-related metabolites and liver function retrospectively in 5 French-Canadian patients from the Kamouraska cohort that was originally described by Saba et al. (2005) and Montpetit et al. (2008). Copper metabolism perturbation and hepatopathy were confirmed in all patients. Studies in patient fibroblasts showed abnormal copper incorporation and retention, and there was reduced expression of the copper-dependent enzymes cytochrome-c-oxidase (see 516030) and Cu/Zn superoxide dismutase (SOD1; 147450) and aberrant intracellular trafficking of ATP7A (300011).

Martinelli et al. (2013) reported an 8-year-old girl, born to consanguineous Sephardic Jewish parents, with alternating diarrhea and constipation, infections, erythematous skin patches, recurrent venous thromboses, hypotonia, and growth and psychomotor delay from infancy. She was later diagnosed with sensorineural hearing loss, hypopigmented and lax skin, ichthyosis, and hepatomegaly. Laboratory testing showed intermittent elevation of transaminases, elevated total bile acids, reduced serum copper and ceruloplasmin, increased serum free copper level, and increased urinary copper excretion. Additional laboratory abnormalities included increased lactate in blood and urine, increased plasma alanine, and borderline elevation of plasma very long chain fatty acids. Increased copper content was identified in a liver biopsy performed at the age of 2 years. At age 7 years, the patient had microcephaly, severely impaired intellectual development, autistic-like features, intractable itching, trichorrhexis nodosa, and hepatomegaly.

Incecik et al. (2018) reported a 10-year-old girl, born to consanguineous Turkish parents, with infantile-onset diarrhea, recurrent infections, ichthyosis, deafness, hypotonia, progressive growth delay, and severely impaired intellectual development. Physical examination at age 10 years showed generalized dry skin, erythematous plaques, and ichthyosiform hyperkeratotic plaques. She had hypotonia, with brisk deep tendon reflexes and muscle weakness in the lower extremities. Serum copper and ceruloplasmin levels were reduced, and plasma very long chain fatty acids were abnormal. An MRI showed brain atrophy.

The transmission pattern of MEDNIK in the families reported by Saba et al. (2005) and Montpetit et al. (2008) was consistent with autosomal recessive inheritance.

By homozygosity mapping in 3 families originating from the Kamouraska region of the province of Quebec with an atypical form of EKV, Saba et al. (2005) excluded GJB3 (603324) on chromosome 1 as a candidate gene; the same approach identified a large region on chromosome 7 that was identical by descent in all affected individuals but not in an unaffected first-degree relative. The assignment was narrowed to a 6.8-Mb region of chromosome 7q22 containing approximately 100 genes, one of which was CX31.3 (GJC3; 611925). Sequencing of the 2 known coding exons of the GJC3 gene revealed no mutations.

Montpetit et al. (2008) identified another family from Quebec with a phenotype similar to that described by Saba et al. (2005). Linkage analysis refined the critical region to 5.3 Mb between D7S2539 and D7S518.

In affected members from 4 families with MEDNIK, Montpetit et al. (2008) identified the same homozygous splice site mutation in the AP1S1 gene (603531.0001). The mutation was identified by linkage analysis followed by candidate gene sequencing. The mutation was predicted to result in a truncated protein with loss of function, but a small amount of an AP1S1 protein with an in-frame deletion was also produced, which may have contributed some residual activity. Knockdown of the Ap1s1 gene in zebrafish resulted in skin and neurologic defects. The AP1S1 gene is involved in protein trafficking between organelles.

In an 8-year-old girl, born of consanguineous Sephardic Jewish parents, with MEDNIK, Martinelli et al. (2013) identified homozygosity for a 1-bp insertion of a G within a string of Gs (nucleotides 356-365) in exon 4 of the AP1S1 gene (603531.0002). In a 10-year-old girl, born to consanguineous Turkish parents, with MEDNIK, Incecik et al. (2018) identified the mutation as a duplication at nucleotide 364 (c.364dupG). Martinelli et al. (2013) found the mutation by whole-exome sequencing and Incecik et al. (2018) found it by targeted gene sequencing. The mutation segregated with the disorder in both families. Martinelli et al. (2013) found that fibroblasts in their patient showed an 80-fold reduction of AP1S1 mRNA expression and absence of AP1S1 protein expression.

Martinelli et al. (2013) treated a patient with MEDNIK who had reduced serum copper and ceruloplasmin, increased serum free copper level, increased urinary copper excretion, and increased liver copper with zinc acetate therapy. With treatment, the patient had a reduction in liver copper, serum free copper, urinary copper, blood lactate, and total bile acids as well as an increase in ceruloplasmin. IQ also increased on zinc acetate therapy.

All 3 families with MEDNIK reported by Saba et al. (2005) were likely to share common ancestors, as they lived in a relatively isolated population descended from founders of French origin who settled south of the St. Lawrence downstream of Quebec City in the 17th and 18th centuries.

See 606945.0025 for another disorder identified in individuals living in the Kamouraska region of the province of Quebec.