（論文要様式３）

旨Hereditary Sensory and Autonomic Neuropathy
Type IID Caused by an SCN9A Mutation
SCN9A 遺伝子変異による新疾患
遺伝性感覚・自律神経性ニューロパチーType IID の確立
袁 軍輝【Introduction and Objective】
Hereditary sensory and autonomic neuropathy (HSAN) encompass a clinically and geneticallyheterogeneous group of disorders that are associated with sensory dysfunction (altered pain andtemperature perception, etc.) and varying degrees of autonomic dysfunction (postural hypotention,sweating abnormalities, etc.). Till date, HSAN has been classified into six main groups on thebasis of their mode of inheritance and clinical features, and eleven HSAN disease-causing genes
have been demonstrated. The objective of this study is to identify the clinical features of Japanesepatients with suspected HSAN on the basis of genetic diagnosis.
【Material and Methods】
On the basis of clinical, electrophysiological, and pathological findings of sural nerve biopsy, nine
Japanese patients with sensory and autonomic nervous dysfunctions, but without multiple motor
nerve involvement, were selected. Using a next-generation sequencing system (Illumina MiSeq),
357 coding exons and exon–intron junctions of eleven known HSAN disease-causing genes andfive related genes (SCN9A, CCT5, PRNP, FLVCR1, and RNF170) were screened.
The protocol of this study was reviewed and approved by the Institutional Review Board ofKagoshima University. All patients and family members provided written, informed consents toparticipate in this study.
【Results】
Using the MiSeq sequencing system, all of the nine cases were genotyped successfully. A
homozygous frameshift mutation, c.3993delGinsTT, was identified in exon 22 of SCN9A fromtwo male patients (patient 1 and 2: 50 and 33 years old, respectively). The clinical phenotype wascharacterized by adolescent or congenital onset with loss of pain and temperature sensation,
autonomic nervous dysfunctions, hearing loss, and hyposmia. This mutation co-segregated withthe patients in their pedigrees, and was subsequently found in a sister of patient 1, who also

exhibited sensory and autonomic nervous system dysfunctions, with recurrent fractures being themost predominant feature. Nerve conduction studies revealed asymmetric sensory nerve
involvement, especially in patient 1. Besides, sural nerve pathology showed loss of large
myelinated fibers in patient 1, while patient 2 showed no evidence of abnormalities.
【Conclusion and Discussion】
In two Japanese families with autosomal recessive HSAN, we identified a novel homozygous
mutation, c.3993delGinsTT, in SCN9A. This loss-of-function mutation is expected to shift thereading frame and generate a premature stop codon. For the first time, we demonstrated that an
SCN9A mutation could generate an HSAN phenotype. We propose this discovery as a new disease
entity, HSAN type IID.
SCN9A encodes the voltage-gated sodium channel (NaV1.7), and is preferentially expressed within
the dorsal root ganglion and sympathetic ganglion neurons and their small-diameter peripheral
axons. The NaV1.7 is crucial for the depolarizing phase of neuronal action potentials, and it seems
to determine the excitability and repetitive firing properties of neurons. Gain-of-function SCN9A
mutations result in several painful disorders due to hyperexcitable nociceptive neurons and states,
such as inherited erythromelalgia (IEM), paroxysmal extreme pain disorder (PEPD), and small
nerve fiber neuropathy (SFN); loss-of-function SCN9A mutations produce no sodium current andgenerate channelopathy-associated insensitivity to pain (CIP), which is characterized bycongenital insensitivity to pain perception and anosmia.
However, the autonomic dysfunction has been regarded as exclusionary criteria for the diagnosisof CIP. In addition, in our patients, the onset age and limited pain insensitivity (distal limb) arealso distinct from the CIP. To sum up, the clinical features of present patients are different fromall of the known SCN9A-related disorders.
On the other hand, in all the reported cases with SCN9A mutation, no definite abnormalities havebeen described using either nerve conduction study or sural nerve pathological examination. But
in our index patients, specifically in patient 1, abnormalities were detected in both the nerve
conduction study and sural nerve pathology, which suggested that the large myelinated fibers wereaffected. Moreover, a mismatch between the distribution of affected fibers and the severity of theloss-of-pain sensations was also uncovered. Taken together, all these findings may indicate thatthe dysfunction of the dorsal root ganglion is more predominant than that of the peripheral nerve.
The age of onset and predominant symptoms were significantly different in three patients. We areable to summarize that one loss-of-function SCN9A mutation can produce heterogeneous
phenotype, and the genotype-phenotype association still requires further research.

（Neurology 2013 Apr 30;80(18) 掲載）