Hereditary sensory and autonomic neuropathy

Hereditary sensory and autonomic neuropathy (HSAN), also known as hereditary sensory neuropathy (HSN), refers to a group of rare neurological conditions characterized by progressive impairment or loss of sensation, primarily affecting the peripheral nervous system. HSAN is less common than Charcot-Marie-Tooth disease.

Classification

Five distinct clinical types of hereditary sensory and autonomic neuropathy have been identified, each characterized by specific clinical features, inheritance patterns, and genetic mutations. The overall incidence of HSAN is estimated at approximately 1 in 25,000 individuals.

Type 1

Main article: Hereditary sensory and autonomic neuropathy type I

HSAN Type 1 typically manifests during adolescence or early adulthood. Symptoms include:

• Reduced sensation (pain, temperature, and touch) initially affecting the legs and feet.
• Progressive involvement of the hands, arms, shoulders, and abdomen.
• Development of painless ulcers on the feet and hands, which may become infected and require amputation.
• Occasional sensorineural hearing loss.
• Muscle wasting and weakness.

Historically, Type 1 has been known by various names, including mal perforant du pied and hereditary perforating ulcers. It includes subtypes such as Charcot-Marie-Tooth type 2B syndrome (HMSN 2B or HSAN type 1C).

Type 1 HSAN follows an autosomal dominant inheritance pattern. It results from mutations in the SPTLC1 gene, disrupting the normal production of the enzyme serine palmitoyltransferase, critical for synthesizing sphingolipids, essential components of myelin. This disruption leads to neuronal degeneration and subsequent sensory loss.

Type 2: Congenital Sensory Neuropathy

HSAN Type 2, also known historically as Morvan's disease, begins in early infancy or childhood. Clinical features include:

• Severe impairment of pain, temperature, and touch sensations.
• Frequent unrecognized injuries leading to ulcerations, infections, and autoamputation.
• Development of Charcot joints due to repetitive unnoticed injuries.
• Mild autonomic disturbances, including impaired reflexes, apnea, and gastroesophageal reflux.
• Loss of lingual fungiform papillae, affecting taste sensation.

Type 2 HSAN follows an autosomal recessive inheritance pattern. It includes two subtypes:

• HSAN2A, caused by mutations in the WNK1 gene.
• HSAN2B, resulting from mutations in the FAM134B gene.

Both mutations cause the death of sensory neurons due to defective protein function and neuronal apoptosis, leading to sensory deficits and autonomic dysfunction.

Type 3: Familial Dysautonomia

Main article: Familial dysautonomia

HSAN Type 3, also called familial dysautonomia or Riley-Day syndrome, primarily affects individuals of Ashkenazi Jewish descent. Symptoms typically present in infancy:

• Poor muscle tone (hypotonia), feeding difficulties, and delayed growth.
• Absence or reduction of tears and reflexes.
• Poor temperature regulation and abnormal responses to pain.
• Orthostatic hypotension, episodic high blood pressure, and poor regulation of autonomic functions.
• Increased susceptibility to respiratory infections and lung damage.
• Developmental delays and impaired coordination.

HSAN Type 3 is inherited in an autosomal recessive manner, caused by mutations in the IKBKAP gene, reducing production of the IKK complex-associated protein (IKAP). This protein reduction impairs nerve cell survival, especially in autonomic and sensory neurons.

Management and Prognosis

Management strategies for HSAN generally focus on supportive care, injury prevention, regular wound care, orthopedic interventions, and symptomatic treatments. Genetic counseling is recommended for affected individuals and their families.

Prognosis varies significantly by type, severity of symptoms, and effectiveness of management. With appropriate medical care, many affected individuals can maintain a normal lifespan.