A number sign (#) is used with this entry because of evidence that fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (FARIMPD) is caused by homozygous mutation in the ATP1A2 gene (182340) on chromosome 1q23.

Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (FARIMPD) is an autosomal recessive syndrome characterized by hypotonia in utero resulting in fetal akinesia with generalized joint contractures and arthrogryposis at birth. Affected newborns have severe respiratory insufficiency at birth requiring ventilation and significant dysmorphic facial features; seizures may also occur. Brain imaging shows variable malformations of cortical development, most commonly polymicrogyria or other gyral anomalies. Death in infancy usually occurs (summary by Monteiro et al., 2020).

Monteiro et al. (2020) reported 3 newborns from 2 unrelated families who had a similar syndromic congenital disorder with features apparent in utero. The pregnancies were complicated by diminished fetal movements, polyhydramnios, generalized edema associated with hydrops fetalis, and generalized joint contractures consistent with fetal akinesia deformation sequence. In utero seizures were suspected in 2 cases, and postnatal seizures occurred in the third case. At birth, the patients had severe hypotonia with insufficient respiratory drive necessitating ventilatory support. They had clenched hands, clubfeet, multiple limb contractures, camptodactyly, and overlapping toes. Dysmorphic facial features included severe microcephaly (down to -8 SD), low anterior hairline, hirsutism, hypertelorism, periorbital fullness, prominent cheeks, large dysmorphic ears, anteverted nares, micrognathia, everted lower lip, and short neck. Brain MRI showed malformations of cortical development, including pachygyria, polymicrogyria, and lissencephaly, cortical calcifications, attenuation of white matter, and enlarged ventricles. One patient had a hypoplastic corpus callosum and cerebellum, overfolded gyri, and glioneuronal heterotopia. Other features observed included umbilical and inguinal hernia, bell-shaped thorax, posterior diaphragmatic hernia, patent foramen ovale, right cardiac ventricular hypertrophy, and congenital hypothyroidism. Both sibs from family 1 died of septic shock and multiorgan failure at 2 months of age. The female infant from family 2 died of respiratory insufficiency soon after birth. The mother in family 1 reported migraine without aura and the mother in family 2 had mild intellectual disability that ran in her family. The fathers had no neurologic symptoms or complaints.

Chatron et al. (2019) reported 4 patients from 2 unrelated families with a lethal syndromic form of polymicrogyria. Three sibs, born of consanguineous Algerian parents (family A), presented prenatally with polyhydramnios, microcephaly, and smooth cortex. The first 2 affected infants died after a few hours of life from respiratory distress; the third affected pregnancy was terminated after prenatal ultrasound showed abnormalities. A 35-week-old affected fetus (patient 4), born of consanguineous Pakistani parents (family B), had microcephaly with unique brain malformations and inguinal hernia; the pregnancy was complicated by polyhydramnios. This patient had previously been reported by Squier and Jansen (2014). Postmortem examination of 2 patients from family A and patient 4 showed features of fetal hypokinesia, including hand contractures and rocker-bottom feet. Neuropathologic studies of 2 patients from family A and patient 4 showed a complex brain malformation pattern with irregular cortical surface, dentato-olivary dysplasia, necrotic and calcified areas in the basal ganglia, and calcified leptomeningeal arteries. The abnormal gyral patterns were consistent with diffuse polymicrogyria. There was also hypoplasia/agenesis of the pyramidal tracts. Family history was notable for monthly migraines in the mother of family A and migraine in both parents of patient 4.

The transmission pattern of FARIMPD in the families reported by Monteiro et al. (2020) was consistent with autosomal recessive inheritance.

In 3 infants from 2 unrelated families with FARIMPD, Monteiro et al. (2020) identified homozygous frameshift mutations in the ATP1A2 gene (182340.0016 and 182340.0017). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Neither were present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but both were predicted to result in a complete loss of ATP1A2 function. All 3 patients died in the perinatal period.

In 3 sibs, conceived of consanguineous Algerian parents, and an unrelated infant, born of consanguineous Pakistani parents, with FARIMPD, Chatron et al. (2019) identified a homozygous frameshift and nonsense mutation, respectively, in the ATP1A2 gene (182340.0018 and 182340.0019). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Both were absent from the gnomAD database. No ATP1A2 immunostaining was detected in brain samples from 2 patients, confirming complete absence of the protein and a loss-of-function effect. Functional studies of the variant were not performed. All patients either died in infancy or the pregnancies were terminated.

Ikeda et al. (2004) found that homozygous knockout of the Atp1a2 gene in mice was embryonic lethal due to severe motor deficits that also abolished respiration by the medullary respiratory center neurons. Analysis of spinal cord motoneurons in mutant mice showed absence of normal spontaneous rhythmic discharges. This was associated with increased inhibitory GABA levels in the extracellular spaces throughout the brain, as well as increased chloride (Cl-) levels within neurons. Ikeda et al. (2004) hypothesized that Atp1a2 normally generates a K+ gradient that fuels extrusion of cytosolic Cl- by KCC2 (SLC12A5; 606726) in respiratory center neurons in the perinatal period. In the absence of this, due to loss of Atp1a2, neurons thus become persistently depolarized and cannot produce action potentials due to the inactivation of fast sodium channels.