Neuropathy, Hereditary Sensory And Autonomic, Type V

A number sign (#) is used with this entry because of evidence that hereditary sensory neuropathy type V (HSAN5) is caused by homozygous mutation in the NGF gene (162030) on chromosome 1p13.

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

Clinical Features

Low et al. (1978) reported a 6-year-old child with congenital sensory neuropathy characterized by a selective loss of pain and thermal sensation affecting the extremities. Nerve conduction studies were normal. Small myelinated fibers were selectively reduced in the sural nerve, and unmyelinated fibers were normal.

Dyck et al. (1983) reported a girl with congenital insensitivity to pain. She responded to tactile stimuli, had preserved tendon reflexes, and had normal motor and sensory nerve conductions. She had self-mutilation of the lips, tongue, and fingers, and mild autonomic involvement, including skin blotching, decreased sweating, and episodic increased body temperature. Nerve conduction velocities were normal, but no somatosensory evoked responses could be recorded over the spine from tibial nerve stimulation. Nerve biopsy showed a selective, virtually complete absence of small myelinated afferent fibers, and a less apparent reduction in the number of unmyelinated fibers. Dyck et al. (1983) referred to the case of Low et al. (1978), and termed the disorder in both cases HSAN type V. Dyck et al. (1983) noted that many similar earlier cases reported as 'congenital indifference to pain' or 'congenital anesthesia' (see 243000), which are characterized by an absence of nerve pathology, were reported before the application of methods to assess the physiologic function of nerve fibers; therefore, some of these cases may have been HSAN4 (256800) or HSAN5.

In an inbred Kashmiri family, Donaghy et al. (1987) described 3 members with a congenital sensory and autonomic neuropathy and corneal opacification. Pain and temperature sensation was lost in the limbs with a resulting mutilating acropathy. Sudomotor function was also impaired, with areas of anhidrosis. Motor function, tendon reflexes, large fiber sensory modalities, and sensory nerve action potentials were normal. Sural nerve biopsy showed a selectively reduced small myelinated nerve fiber population. Unmyelinated axons showed normal density with some evidence of degeneration. Corneal histology showed neurotrophic keratitis. The 3 affected individuals occurred in 2 sibships related to each other as first cousins once removed and were children of first-cousin parents.

Itoh et al. (1999) reported a pair of female monozygotic twin infants who had generalized loss of pain sensation without impairment of other sensory modalities or diaphoretic function. Sural nerve biopsy showed that the number of small myelinated fibers was reduced and that of unmyelinated fibers was normal or mildly reduced. The authors suggested a diagnosis of HSAN5.

Karkashan et al. (2002) reported 2 sibs from Saudi Arabia with congenital insensitivity to pain. Three additional members of related families who could be traced back to the same grandfather were also affected. All patients had normal intelligence, normal sweating, and normal appreciation of other sensory modalities. All had painless injuries resulting in cuts, bruises, and fractures.

Einarsdottir et al. (2004) described a large multigenerational consanguineous family from northern Sweden suffering from loss of pain perception but with most other neurologic functions intact. The patients suffered from a severe loss of deep pain perception that prevented them from feeling pain from bone fractures and joints; heat perception was also impaired. Decreased deep pain perception led to destroyed joints (Charcot joints) in childhood. Most other neurologic functions including sweating and mental abilities were intact. A number of additional family members suffered from a less severe phenotype presenting as joint problems mostly in the feet and knees and resulting in Charcot joints later in life. Neurophysiologic and neuropathologic findings showed that the patients in this family suffered from a peripheral neuropathy with a severe reduction of unmyelinated nerve fibers and a moderate loss of thin myelinated nerve fibers. Einarsdottir et al. (2004) classified the neuropathy in this family as HSAN5, which is characterized by loss of pain perception, impaired temperature sensitivity, ulcers, and in some cases self-mutilation, and in which the autonomic involvement is variable (Hilz, 2002).

Carvalho et al. (2011) reported a consanguineous Emirati Bedouin family in which 5 sibs ranging in age from 2 to 12 years had HSAN5 and mild mental retardation. The first medical problem was biting of lips, tongue, and digits without apparent discomfort or pain. None could discriminate heat and cold or detect hot spicy food, and all had anhidrosis. Mild mental retardation was evident by the age of 4 years. With age, all developed a prematurely aged appearance, with malar hypoplasia, sunken eyes, and loss of teeth. All had suffered multiple, painless, injuries of varying severity and showed poor wound healing, which the authors suggested may reflect a mild immunodeficiency. There was a normal response to insect bites, which may serve as a proxy for an intradermal histamine flare test. In a reevaluation of the family reported by Carvalho et al. (2011), Hepburn et al. (2014) noted that patients with HSAN5 also had frequent severe Staphylococcus aureus infections of the skin, teeth, joints, and bone, suggesting a pathogen-specific immune defect.

Mapping

In 3 severely affected members of a large consanguineous family from northern Sweden with HSAN5, Einarsdottir et al. (2004) screened for shared homozygosis regions. They identified an 8.3-Mb region on chromosome 1p13.2-p11.2 shared by the affected members.

Molecular Genetics

Einarsdottir et al. (2004) demonstrated that all 3 severely affected family members of the Swedish family with HSAN5 studied by them were homozygous for a 661C-T transition in the gene encoding nerve growth factor-beta (NGFB; 162030). The mutation was predicted to result in a substitution of tryptophan for arginine-211 (162030.0001) in a highly conserved region of the protein.

Carvalho et al. (2011) identified a homozygous loss of function mutation in the NGFB gene (162030.0002) in a consanguineous Emirati Bedouin family with HSAN5 and mild mental retardation. The findings expanded the phenotype of HSAN5 to be closer to that of HSAN4, indicating that there is a phenotypic spectrum due to changes in the NGF/TRKA signaling pathway.