A number sign (#) is used with this entry because of evidence that hereditary sensory and autonomic neuropathy type IX with developmental delay (HSAN9) is caused by homozygous or compound heterozygous mutation in the TECPR2 gene (615000) on chromosome 14q32.

Hereditary sensory and autonomic neuropathy type IX with developmental delay (HSAN9) is an autosomal recessive neurodevelopmental and neurodegenerative disorder. Clinical features include global developmental delay and intellectual disability, axial and appendicular hypotonia, dysarthria, and an abnormal gait that is often described as ataxic. Other features may include peripheral neuropathy, hyporeflexia, and autonomic dysfunction (summary by Neuser et al., 2021).

For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1 (162400).

Oz-Levi et al. (2012) reported 5 individuals from 3 apparently unrelated Jewish Bukharian families with a disorder that the authors designated spastic paraplegia-49 (SPG49). Affected individuals presented during the second year of life with hypotonia and developmental delay. Dysmorphic features included short stature, mild brachycephalic microcephaly, round face, low anterior hairline, dental crowding, short broad neck, and a chubby appearance. They had delayed psychomotor development with moderately to severely impaired intellectual development. A spastic, rigid, ataxic gait with areflexia developed at the end of the first decade. Other features included dysarthria, hypomimic facies, and dysmetria. All also had recurrent respiratory infections due to gastroesophageal reflux disease. An unusual feature was recurrent episodic central apnea initially occurring during sleep, but evolving into the wake state. Four patients had episodes of decreased alertness, aggravation of hypotonia, and inefficient respiration requiring mechanical ventilation. One patient died at age 5.5 years from aspiration. Two sibs had infrequent seizures. Brain MRI of 2 individuals showed a thin corpus callosum and cerebral and cerebellar atrophy.

Heimer et al. (2016) described 3 unrelated patients, 2 born to nonconsanguineous Ashkenazi parents and 1 born to mixed Ashkenazi/Tunisian and Yamani/Kurdish parents, with moderately to severely impaired intellectual development, dysmorphic features, and a sensory autonomic neuropathy. Patient 1 had gastroesophageal reflux and aspiration in the first year of life, which progressed to chronic lung disease. He had delayed global development and started walking after age 3 years with unstable gait. At age 4 he had deceleration of his head growth, facial hypotonia, pectus carinatum, hyporeflexia, and decreased sensitivity to pain. He had mild bilateral hearing loss, astigmatism, and myopia. He died at age 6 following a severe pulmonary infection. Patient 2 had gastroesophageal aspiration and developed chronic lung disease necessitating tracheostomy and nighttime ventilation. He had microcephaly, moderately to severely impaired intellectual development, decreased sensitivity to pain, and delayed walking. Examination at age 7 years showed hypotonia, areflexia, truncal titubation, and ataxic gait. At the age of 18 he was wheelchair dependent, required nighttime ventilation, and had recurrent pulmonary infections and encephalopathic events. Brain MRI demonstrated mild cerebral and vermian atrophy. Patient 3 had recurrent vomiting and aspiration pneumonia since birth. From infancy he had episodes of dehydration, cold extremities, postural hypotension, fevers, and hypertension, and he appeared to have reduced pain sensitivity. He had delayed psychomotor development. Examination at age 4 showed axial and limb hypotonia, areflexia, and decreased head circumference.

Covone et al. (2016) described a 16-year-old girl, born to nonconsanguineous Italian parents, who developed recurrent vomiting and unstable ambulation at 4 years of age. Neurologic examination at age 9 demonstrated strabismus, reduced reflexes in the upper limbs, and weakness in the lower limbs. At age 10 she had muscle atrophy and hypotonia of the trunk and upper limbs, scoliosis, dysarthric speech and ocular apraxia. She lost the ability to ambulate at age 12. At age 13, she developed respiratory insufficiency in the setting of an infection and required a tracheostomy and mechanical ventilation. On examination at age 15, she had tetraparesis with hypotonia of upper limbs and hypertonia of lower limbs. Brain MRI showed a mild global thinning of the corpus callosum. EMG showed a neurogenic pattern at 4 limbs. A muscle biopsy demonstrated secondary signs of a motor neuron defect.

Patwari et al. (2020) reported a patient who had a complex respiratory pattern, including hypopnea and central apnea, detected on a sleep study at 32 months of age, which progressed to a Biot (ataxic) breathing pattern and central apnea. On examination at age 4 years, her height and weight were at the 5th percentile and she had low axial tone and a poorly coordinated gait. She also had global developmental delay and speech impairment.

Neuser et al. (2021) reported clinical findings in 17 patients, including 2 sib pairs, from 15 families segregating HSAN9. The patients ranged in age from 16 months to 15 years. All of the patients had global developmental delay/impaired intellectual development, which was mild in 1 patient, moderate in 7 patients, and severe in 8 patients. Neurologic manifestations included hypotonia (17/17), gait ataxia (11/11), lower limb hyporeflexia (13/17), and dysarthria (6/8). Autonomic dysfunction was seen in 5 patients. Central respiratory dysregulation was common, resulting in central nocturnal (8/13) and/or daytime (5/16) hypoventilation, and dysphagia (9/17). Seven patients had short stature, 7 had brachycephaly, and 4 had microcephaly. Dysmorphic features seen in some patients included short neck, synophrys, and triangular-shaped facies. Five patients had skeletal abnormalities, including lumbar kyphosis, barrel-shaped chest, or neck hyperextension.

The transmission pattern of HSAN9 in the families reported by Oz-Levi et al. (2012) was consistent with autosomal recessive inheritance.

By exome sequencing of 4 Jewish Bukharian patients with HSAN9, Oz-Levi et al. (2012) identified a homozygous frameshift mutation in the TECPR2 gene (615000.0001). Haplotype analysis suggested a founder effect. Skin fibroblasts from an affected individual showed impaired expression of the autophagocytic proteins SQSTM1 (601530) and MAP1LC3B (609604) in response to various conditions that should have increased the levels of these proteins. The findings suggested that TECPR2 mutations cause impairment of the intracellular autophagy pathway, with attenuation of delivery of targeted proteins to the lysosome.

In 3 unrelated patients with HSAN9, Heimer et al. (2016) identified homozygous or compound heterozygous mutations in the TECPR2 gene (615000.0001-615000.0003). The mutations, which were identified by whole-exome sequencing or Sanger sequencing, segregated with disease in each family.

In a patient with HSAN9, Patwari et al. (2020) identified compound heterozygous mutations the TECPR2 gene (615000.0004; 615000.0005).

In a 16-year-old Italian girl HSAN9, Covone et al. (2016) identified compound heterozygosity for 2 missense mutations in the TECPR2 gene (NM_014844.3): c.898G-A (G300R) and c.2708C-T (T903M). This patient also carried a mutation in the SPG7 gene (602783), which was present in her unaffected father. The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies were not performed.

In 17 patients in 15 families segregating HSAN9, Neuser et al. (2021) identified homozygous or compound heterozygous mutations in the TECPR2 gene (see, e.g., 615000.0001; 615000.0002; 615000.0006-615000.0007). The mutations were identified by whole-exome sequencing, genetic panel testing, or targeted Sanger sequencing.