This report describes neuropathy, hereditary sensory and autonomic, type IA (HSAN1A), which exhibits autosomal dominant inheritance. The human gene implicated in this disease is serine palmitoyltransferase 1 (SPTLC1), which is a key enzyme in sphingolipid biosynthesis. There is a single orthologous gene in Drosophila, Spt-I, for which classical hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
The human SPTLC1 gene has not been introduced into flies.
Loss-of-function alleles of Dmel\Spt-I result in lethality during the first larval instar. Glial-specific knockdown of Spt-I, effected by RNAi, results in defects in axonal ensheathment by the glia cells. Genetic and physical interactions for Dmel\Spt-I have been described; see below and in the gene report for Spt-I.
Variant(s) implicated in human disease tested (as analogous mutation in fly gene): C129W in the fly Spt-I gene (corresponds to C133W in the human SPTLC1 gene). Neuronal expression of the disease-related variant of Dmel\Spt-I results in morphological defects in synapse growth and dendritic arborization. Ubiquitous expression is mildly toxic; complete toxicity is observed if food is supplemented with alanine.
The serine palmitoyltransferase subunit SPTLC2 is also implicated in a subtype of hereditary sensory and autonomic neuropathy; see the human disease model report 'neuropathy, hereditary sensory and autonomic, type IB' (FBhh0001015).
[updated May 2019 by FlyBase; FBrf0222196]
Hereditary sensory and autonomic neuropathies (HSN/HSAN) are clinically and genetically heterogeneous disorders of the peripheral nervous system that predominantly affect the sensory and autonomic neurons (Auer-Grumbach, 2013; pubmed:23931820).
Hereditary sensory and autonomic neuropathies (HSANs) occur much less frequently than do the primary hereditary motor sensory neuropathies (HMSNs) (http://www.uptodate.com/contents/hereditary-sensory-and-autonomic-neuropathies).
The hereditary sensory and autonomic neuropathies (HSAN), which are also referred to as hereditary sensory neuropathies (HSN), are a genetically and clinically heterogeneous group of disorders associated with sensory dysfunction, typically characterized by characterized by insensitivity to pain and resulting in injury to the fingers, tongue, lips, and other distal appendages. [from MIM:162400, MIM:616488; 2017.07.10]
[NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IA; HSAN1A](https://omim.org/entry/162400)
[SERINE PALMITOYLTRANSFERASE, LONG-CHAIN BASE SUBUNIT 1; SPTLC1](https://omim.org/entry/605712)
Hereditary sensory neuropathy type IA (HSN1A) is an axonal form of hereditary motor and sensory neuropathy distinguished by prominent early sensory loss and later positive sensory phenomena including dysesthesia and characteristic "lightning" or "shooting" pains. Loss of sensation can lead to painless injuries, which, if unrecognized, result in slow wound healing and subsequent osteomyelitis requiring distal amputations. HSN1A is often associated with progressive sensorineural deafness. Motor involvement is present in all advanced cases and can be severe. After age 20 years, the distal wasting and weakness may involve proximal muscles so that a person in his/her 60s or 70s may require a wheelchair for mobility. [Gene Reviews, Hereditary Sensory Neuropathy Type IA; 2017.01.12]
HSAN1 is a dominantly inherited sensorimotor axonal neuropathy with onset in the first or second decades of life. [from MIM:162400; 2015.01.12]
Hereditary sensory neuropathy type IA (HSAN1A) is caused by heterozygous mutation in the SPTLC1 gene (autosomal dominant).
Sphingolipids occur chiefly in the cell membranes of the brain and nervous tissue. [from MIM:162400; 2015.01.12]
Serine palmitoyltransferase 1 (SPTLC1) is the key enzyme in sphingolipid biosynthesis. It catalyzes the first and rate-limiting step. [from MIM:605712; 2015.01.12]
One to one: 1 human to 1 Drosophila.
High-scoring ortholog of human SPTLC1 (1 Drosophila to 1 human). Dmel\Spt-I shares 53% identity and 71% similarity with human SPTLC1.
