Impaired Copper Metabolism in a Patient With Short Gut and IDEDNIK Syndrome

Abstract

IDEDNIK syndrome (intellectual disability, enteropathy, deafness, neuropathy, ichthyosis, and keratoderma; OMIM: 242150, MEDNIK syndrome: 609313, KIDAR: 242150) is a recently recognized autosomal recessive neurocutaneous disorder resulting from pathogenic variants of either AP1S1 or AP1B1 [1]. It is associated with low serum copper and ceruloplasmin levels secondary to perturbations of intracellular copper transport. Patients with short bowel syndrome can also develop hypocupremia from impaired copper absorption in the small intestine [2]. Disorders of copper transport should be considered in any infant presenting with hypocupremia.

This 30-month-old girl was delivered at 32 weeks gestational age by Caesarean section for absent fetal movements, though she required minimal resuscitation. She did not tolerate feedings, and laparotomy confirmed small bowel ischemia requiring resection of 26 cm of the terminal small intestine. She exhibited erythematous scaling plaques with hyperpigmented borders, consistent with erythrokeratodermia variabilis. Profound bilateral sensorineural hearing was discovered at 4 months of age. At 11 months of age, she began experiencing recurrent episodes of febrile status epilepticus. She remained TPN-dependent secondary to intestinal failure. Elevated serum transaminase levels and depressed serum copper and ceruloplasmin levels were initially attributed to short bowel syndrome and TPN-induced hepatopathy (see Table 1).

Magnetic resonance imaging of the brain at 22 months of age documented supratentorial global white matter loss with retained myelin maturation (see Figure 1). Nerve conduction studies at 24 months of age revealed an axonal polyneuropathy predominantly affecting sensory nerves. Epidermal nerve fiber density studies were normal.

Examination at 30 months of age revealed a normocephalic head size, lack of dysmorphic features, depressed deep tendon reflexes, and profound developmental delay.

At 10 months of age, genetic evaluation included chromosome microarray, which demonstrated 2.06% regions of homozygosity due to parental consanguinity but was otherwise uninformative. Subsequently, proband exome sequencing identified homozygous, likely pathogenic variants: AP1S1(NM_001283.5):c291+2T>A (p.=?), ClinVarID:851525 in intron 3 of AP1S1 confirming the diagnosis of IDEDNIK syndrome. Both parents were confirmed to be heterozygous carriers of this variant. Enteral zinc acetate supplementation, starting at 15 months of age, resulted in modestly improved serum transaminase, copper, and ceruloplasmin levels (see Table 1), though she remains profoundly delayed.

Differential diagnosis for developmental delay in the setting of hypocupremia includes Wilson's disease, Menkes disease, short bowel syndrome, and IDEDNIK syndrome. Wilson's disease is a copper transport disorder causing reduced secretion of copper from the liver into bile for subsequent elimination via the gut. Pathogenic variants of ATP7B also impair copper incorporation into apoceruloplasmin, the precursor for ceruloplasmin, for excretion through the renal system. Copper accumulates within the liver, brain, eyes, and other organs, where it produces toxic effects. Treatment is with copper chelation, a low copper diet, and enteral zinc supplementation to compete with enteral copper absorption from the duodenum and small bowel.

Menkes disease is another copper transport disorder caused by pathogenic variants of ATP7A leading to malabsorption of copper from the duodenum and small intestine. This causes copper deficiencies in the brain, liver, and blood. Early treatment with copper histidine restores serum copper levels and partially mitigates progressive neurological deterioration.

Low serum copper and ceruloplasmin levels have been reported in patients with short bowel syndrome, even with TPN supplementation [2, 3].

IDEDNIK syndrome has been linked to pathogenic variants of either AP1B1 on 22q12 or AP1S1 on 7q22.1. Both genes encode for subunits of the adapter-related protein complex 1. This protein complex regulates clathrin-coated vesicle assembly, protein cargo sorting, and vesicular trafficking of copper transporters [4]. Affected individuals demonstrate altered copper metabolism with reduced serum levels of copper and ceruloplasmin, hepatic copper accumulation, and cholestasis, similar to that seen in Wilson's disease, albeit by a different mechanism of impaired copper transport. Early identification of IDEDNIK and treatment with enteral zinc acetate may reduce the development of hepatic cholestasis and improve neurological function [5].

Stephen Deputy: conceptualization, writing – original draft, writing – review and editing.

Formal IRB approval was not required for this case report since all patient identifying information has been removed.

The author declares no conflicts of interest.