A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with epilepsy and hemochromatosis (NEDEPH) is caused by hemizygous mutation in the PIGA gene (311770) on chromosome Xp22.

Neurodevelopmental disorder with epilepsy and hemochromatosis (NEDEPH) is an X-linked recessive disorder characterized by global developmental delay, early-onset seizures, and progressive systemic iron deposition particularly affecting the liver and resulting in juvenile-onset hemochromatosis. Variable additional features may include joint contractures, visual or hearing impairment, and skin abnormalities (summary by Swoboda et al., 2014 and Muckenthaler et al., 2022).

Swoboda et al. (2014) reported a 3-generation family in which 3 males had a similar neurodegenerative epileptic encephalopathy inherited in an X-linked recessive pattern. The proband died at age 7 years; his affected brother died at age 16 years; their affected nephew was 15 years old at the time of the report. All patients had normal early development until the onset of recurrent seizures between 7 and 9 months of age. Thereafter, all showed regression of psychomotor development and an encephalopathic phenotype with abnormal movements, myoclonus, spasticity, abnormal eye movements, lack of speech, and profound intellectual disability. All developed deceleration of head growth resulting in microcephaly. Two patients were cortically blind and deaf, and 2 had joint contractures. All 3 patients had hepatomegaly, and 1 died of liver failure at age 16 years. Liver microscopy in this patient showed macro- and micronodular cirrhosis with extensive iron deposition; iron deposition was also found in other internal organs. Neuropathologic examination of this patient showed cortical and cerebellar atrophy, neuronal loss, spongy gliosis, and scant iron deposition in some brain regions. The 15-year-old living patient was profoundly disabled, and serum iron studies suggested systemic iron overload. In addition to the neurologic features, all patients had ichthyosis or seborrheic dermatitis with dryness and desquamation of plaque-like scales. Oral abnormalities included microdontia, widely spaced and pointed teeth, and gingival overgrowth. Swoboda et al. (2014) that the disorder in their family be called ferro-cerebro-cutaneous syndrome (FCCS).

Muckenthaler et al. (2022) reported 3 unrelated male patients, ranging from 2 to 13 years of age, with a similar neurodevelopmental disorder associated with iron overload. All 3 patients were initially brought to medical attention because of their neurologic symptoms, which included global developmental delay and onset of focal and generalized seizures within the first year of life. Other variable features included hypospadias, cryptorchidism, and somatomegaly. Patient 2 had cortical visual impairment and ectodermal anomalies, including ichthyosis, pigmented areas on the neck, and widely-spaced teeth. Laboratory studies showed increased serum ferritin, increased serum iron levels, high transferrin saturation, high serum alkaline phosphatase, and low hepcidin (606464).

The transmission pattern of NEDEPH in the family reported by Swoboda et al. (2014) was consistent with X-linked recessive inheritance.

In 2 affected males from a large family with NEDEPH, Swoboda et al. (2014) identified a hemizygous in-frame 3-bp deletion in the PIGA gene (leu110del; 311770.0016). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Flow cytometric analysis of the proband's granulocytes showed decreased cell surface levels of some GPI-anchored proteins, although CD59 (107271) expression on red blood cells was normal, suggesting that the mutant protein had some residual activity.

In 3 unrelated patients with NEDEPH, Muckenthaler et al. (2022) identified hemizygous missense mutations in the PIGA gene (R77Q, 311770.0018; L344P, 311770.0019; and S127L, 311770.0020). The mutations, which were found by exome sequencing or sequencing of a gene panel, were all inherited from an unaffected mother. A subpopulation of patient blood cells showed a slight reduction of GPI-anchored proteins, suggesting that the mutations were hypomorphic and retained some residual activity. CRISPR/Cas12a-mediated knockdown of PIGA in Hep3B liver cells eliminated the cell surface expression of GPI-anchored proteins CD59 and hemojuvelin (HJV; 608374), as well as caused decreased expression of hepcidin (606464) compared to controls. These findings indicated disruption of iron homeostasis. Transfection with wildtype PIGA rescued these defects, but expression of the L344P or R77Q mutations did not rescue hepcidin mRNA levels, consistent with a functional deficiency of PIGA. PIGA knockdown also reduced the levels of ceruloplasmin (CP), a GPI-anchored ferroxidase required for efficient cellular iron export. Reduced CP protein expression may aggravate iron overload and contribute to neurologic symptoms. The authors noted that the missense mutations had less deleterious effects than complete loss-of-function alleles, suggesting that the missense variants have residual function. These hypomorphic alleles could explain the milder neurologic phenotype, which allowed for sufficiently long survival for the iron overload phenotype to manifest.

Associations Pending Confirmation

Flores-Torres et al. (2021) reported a male infant with hemochromatosis associated with a hemizygous ala103-to-thr (A103T) variant of uncertain significance in the PIGA gene that was found by whole-exome sequencing. He was born at 37 weeks' gestation with intrauterine growth retardation and patent ductus arteriosus; the pregnancy was complicated by oligohydramnios. Laboratory studies showed hyperbilirubinemia, elevated liver enzymes, and increased serum ferritin. Abdominal ultrasound indicated iron deposition in the liver and renal cortex, and liver biopsy showed iron deposition, cholestasis, and extramedullary hematopoiesis, consistent with neonatal hemochromatosis. The patient also had dysmorphic features, including overriding sutures, prominent forehead, receding hairline, and anteverted nares. However, at age 11 months, he had normal liver enzymes, ferritin, and bilirubin; neurodevelopment was also normal. The authors speculated that the PIGA variant may retain partial function, thus explaining the unusually mild clinical course in this patient. The report demonstrated that neonatal hemochromatosis is not always lethal.