Hypotonia, Hypoventilation, Impaired Intellectual Development, Dysautonomia, Epilepsy, And Eye Abnormalities

A number sign (#) is used with this entry because of evidence that hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities (HIDEA) is caused by homozygous or compound heterozygous mutation in the P4HTM gene (614584) on chromosome 3p21.

Description

Hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities (HIDEA) is an autosomal recessive neurodevelopmental syndrome characterized by global developmental delay, poor or absent speech, hypotonia, variable ocular movement and visual abnormalities, and respiratory difficulties, including hypoventilation, and sleep apnea. Patients may have significant breathing problems during respiratory infections that may lead to early death (summary by Rahikkala et al., 2019).

Clinical Features

Kaasinen et al. (2014) reported a large Finnish kindred in which 6 individuals had a similar intellectual developmental disorder. The patients lived in the same village, and extensive genealogic work showed a common distant ancestor from the 17th century. The patients, who ranged in age from 14 to 59 years, had delayed walking at about 3.5 to 5 years, although a few never achieved independent walking. The patients were nonverbal, although 1 could speak in simple sentences. All had profoundly impaired intellectual development corresponding to the level of infancy. From early on, the patients were noted to have abnormal eye movements, including rotary pendular nystagmus, exotropia, and strabismus, as well as other ocular anomalies, including poor visual fixation, myopia, hyperopia, astigmatism, and pale retinal pigmentation. Three patients had infantile seizures, and 1 was diagnosed with epilepsy at age 22 years; the other 2 patients had a sleep behavior disorder. Skeletal features included scoliosis, kyphosis, pes planovalgus, mild elbow contractures, hip and knee flexion while walking, and valgus knee deformities. They also had coarse facial features, such as low nasal bridge, prominent forehead and chin, thick lips, and thick hair, as well as a tendency to obesity. Several other presumably affected deceased individuals were noted in the family, but not described in detail.

Rahikkala et al. (2019) reported 7 patients from 4 unrelated families with HIDEA syndrome and reviewed the large Finnish family reported by Kaasinen et al. (2014). The families were Finnish, American, Turkish, and Syrian. Four patients died between 7 months and 8 years of age, whereas 3 were alive between 3 and 18 years of age. One patient from the family reported by Kaasinen et al. (2014) died at 61 years of age. The patients had global developmental delay, hypotonia, delayed walking or inability to walk, severe to profound intellectual disability, and poor or absent speech. Those who could walk had a wide-based unsteady gait. Most had seizures associated with EEG abnormalities, mainly multifocal spikes; 1 patient did not have overt seizures, but did have EEG abnormalities. The patients had common respiratory difficulties, including bradypnea and hypoventilation, and obstructive or restrictive sleep apnea, often requiring BiPAP at night. Most patients had recurrent pneumonia, usually associated with significant respiratory distress and sometimes resulting in death. Eye abnormalities included rotary nystagmus, myopia, hyperopia, astigmatism, strabismus, exotropia, achromic fundi, cortical blindness, and optic atrophy. A few patients had evidence of autonomic dysfunction, including hypo- or hyperthermia and constipation. Muscle biopsy from 4 patients was suggestive of defects in mitochondrial function. None of the patients had renal anomalies.

Inheritance

The transmission pattern of HIDEA in the families reported by Rahikkala et al. (2019) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 6 patients from a large Finnish kindred with HIDEA, Kaasinen et al. (2014) identified 3 potentially damaging homozygous variants in 3 different genes within the candidate interval at chromosome 3p22-p21 that was identified by linkage analysis. The variants, which occurred in the P4HTM, TKT (606781), and USP4 (603486) genes, all segregated with the disorder in the kindred. In a follow-up report of this family and of 4 other families with a similar disorder, Rahikkala et al. (2019) confirmed that the pathogenic variant responsible for the phenotype was in the P4HTM gene. Five different homozygous or compound heterozygous mutations were found in affected members from the 5 families (614584.0001-614584.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. In vitro functional expression studies of 3 of the P4HTM variants showed that they caused a significant decrease in the amount of soluble protein compared to wildtype. These findings suggested that the mutations caused structural abnormalities and improper folding of the protein, resulting in a loss of function.

Animal Model

Leinonen et al. (2016) found that P4htm -/- mice were fertile and had normal life span. Lack of P4htm stabilized Hif1-alpha in cortical neurons under normoxia, whereas in hypoxia it increased expression of certain HIF target genes in tissues with high endogenous P4htm expression levels. Morphologic analysis of P4htm -/- kidneys revealed that, from the age of about 10 months, renal erythropoietin levels increased, leading to accumulation of lipid-containing lamellar bodies in kidney tubuli, inflammation and fibrosis, and after the age of 1 year, glomerular sclerosis and albuminuria. Lack of P4htm resulted in age-related retinal thinning, rosette-like infoldings, and drusen-like structure accumulation in RPE, characteristic of age-related macular degeneration (AMD; see 603075). P4htm -/- mice showed compromised photoreceptor recycling, and electroretinogram analysis revealed impaired cone pathway in adult mice and cone and rod deficiency in middle-aged mice. Leinonen et al. (2016) concluded that P4HTM is required for normal vision and is a candidate for AMD.