Exploring CNS Involvement in Pain Insensitivity in Hereditary Sensory and Autonomic Neuropathy Type 4: Insights from Tc-99m ECD SPECT Imaging.

Hereditary sensory and autonomic neuropathy type 4 (HSAN4), also known as congenital insensitivity to pain with anhidrosis (CIPA), is a rare genetic disorder caused by NTRK1 gene mutations, affecting nerve growth factor signaling. This study investigates the central nervous system's (CNS) involvement and its relation to pain insensitivity in HSAN4. We present a 15-year-old girl with HSAN4, displaying clinical signs suggestive of CNS impact, including spasticity and a positive Babinski's sign. Using Technetium-99m ethyl cysteinate dimer single-photon emission computed tomography (Tc-99m ECD SPECT) imaging, we discovered perfusion deficits in key brain regions, notably the cerebellum, thalamus, and postcentral gyrus. These regions process pain signals, providing insights into HSAN4's pain insensitivity. This study represents the first visualization of CNS perfusion abnormality in an HSAN4 patient. It highlights the intricate relationship between the peripheral and central nervous systems in HSAN4. The complexity of HSAN4 diagnosis, involving potential unidentified genes, underscores the need for continued research to refine diagnostic approaches and develop comprehensive treatments.

Reduced Myocardial Uptake of 123I-MIBG in Congenital Insensitivity to Pain With Anhidrosis.

ABSTRACT: A 30-year-old man presented with repeated episodes of painless injuries in his feet and abnormally high body temperature. He was diagnosed with congenital insensitivity to pain with anhidrosis-a rare hereditary peripheral neuropathy characterized by decreased pain, reduced sweating, and autonomic neuropathy. Congenital insensitivity to pain with anhidrosis is also called hereditary sensory and autonomic neuropathy type IV. 123I-MIBG myocardial scintigraphy showed reduced myocardial uptake (heart-to-mediastinum ratio: 1.56 and 1.42 in the early and late phases, respectively; washout ratio, 49%), indicating autonomic dysfunction. This finding may contribute to the diagnosis of congenital insensitivity to pain with anhidrosis and the semiquantitative evaluation of an autonomic dysfunction.

Actualización en la valoración de los nervios periféricos mediante resonancia magnética: de la neurografía morfológica a la funcional / Update in the evaluation of peripheral nerves by MRI, from morphological to functional neurography

El estudio los nervios periféricos (NNPP) mediante técnicas de imagen ha experimentado un notable crecimiento en la última década. Más allá del abordaje clásico y todavía vigente mediante ecografía de los NNPP, el desarrollo de nuevas técnicas neurográficas a partir de secuencias morfológicas convencionales (incluyendo estudios 3D isotrópicos con supresión grasa) está permitiendo valorar los distintos NNPP y plexos incluyendo pequeñas ramas terminales sensitivas y/o motoras con gran precisión. El uso de secuencias potenciadas en difusión (DWI) y tensor de difusión (DTI) ha permitido abrir un nuevo horizonte en los estudios de neurografía. Este nuevo abordaje proporciona información morfológica y funcional acerca de la estructura interna y fisiopatología de los NNPP y las distintas patologías relacionadas con ellos. En esta actualización realizamos una puesta al día de las distintas modalidades de neurografía mediante resonancia magnética disponibles para el estudio de los NNPP, con especial atención a las nuevas secuencias basadas en difusión

Imaging studies of peripheral nerves have increased considerably in the last ten years. In addition to the classical and still valid study by ultrasound, new neurographic techniques developed from conventional morphological sequences (including 3D isotropic studies with fat suppression) are making it possible to assess different peripheral nerves and plexuses, including small sensory and/or motor branches, with great precision. Diffusion-weighted sequences and diffusion tensor imaging have opened a new horizon in neurographic studies. This new approach provides morphological and functional information about the internal structure and pathophysiology of the peripheral nerves and diseases that involve them. This update reviews the different MR neurography techniques available for the study of the peripheral nerves, with special emphasis on new sequences based on diffusion

De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy.

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous disorder of the peripheral nervous system. Biallelic variants in SLC12A6 have been associated with autosomal-recessive hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC). We identified heterozygous de novo variants in SLC12A6 in three unrelated patients with intermediate CMT. METHODS: We evaluated the clinical reports and electrophysiological data of three patients carrying de novo variants in SLC12A6 identified by diagnostic trio exome sequencing. For functional characterisation of the identified variants, potassium influx of mutated KCC3 cotransporters was measured in Xenopus oocytes. RESULTS: We identified two different de novo missense changes (p.Arg207His and p.Tyr679Cys) in SLC12A6 in three unrelated individuals with early-onset progressive CMT. All presented with axonal/demyelinating sensorimotor neuropathy accompanied by spasticity in one patient. Cognition and brain MRI were normal. Modelling of the mutant KCC3 cotransporter in Xenopus oocytes showed a significant reduction in potassium influx for both changes. CONCLUSION: Our findings expand the genotypic and phenotypic spectrum associated with SLC12A6 variants from autosomal-recessive HMSN/ACC to dominant-acting de novo variants causing a milder clinical presentation with early-onset neuropathy.

Development of MRC Centre MRI calf muscle fat fraction protocol as a sensitive outcome measure in Hereditary Sensory Neuropathy Type 1.

OBJECTIVES: Hereditary sensory neuropathy type 1 (HSN1) is a rare, slowly progressive neuropathy causing profound sensory deficits and often severe motor loss. L-serine supplementation is a possible candidate therapy but the lack of responsive outcome measures is a barrier for undertaking clinical trials in HSN1. We performed a 12-month natural history study to characterise the phenotype of HSN1 and to identify responsive outcome measures. METHODS: Assessments included Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNSv2), CMTNSv2-Rasch modified, nerve conduction studies, quantitative sensory testing, intraepidermal nerve fibre density (thigh), computerised myometry (lower limbs), plasma 1-deoxysphingolipid levels, calf-level intramuscular fat accumulation by MRI and patient-based questionnaires (Neuropathic Pain Symptom Inventory and 36-Short Form Health Survey version 2 [SF-36v2]). RESULTS: 35 patients with HSN1 were recruited. There was marked heterogeneity in the phenotype mainly due to differences between the sexes: males generally more severely affected. The outcome measures that significantly changed over 1 year and correlated with CMTNSv2, SF-36v2-physical component and disease duration were MRI determined calf intramuscular fat accumulation (mean change in overall calf fat fraction 2.36%, 95% CI 1.16 to 3.55, p=0.0004), pressure pain threshold on the hand (mean change 40 kPa, 95% CI 0.7 to 80, p=0.046) and myometric measurements of ankle plantar flexion (median change -0.5 Nm, IQR -9.5 to 0, p=0.0007), ankle inversion (mean change -0.89 Nm, 95% CI -1.66 to -0.12, p=0.03) and eversion (mean change -1.61 Nm, 95% CI -2.72 to -0.51, p=0.006). Intramuscular calf fat fraction was the most responsive outcome measure. CONCLUSION: MRI determined calf muscle fat fraction shows validity and high responsiveness over 12 months and will be useful in HSN1 clinical trials.

Novel NTRK1 mutations in Chinese patients with congenital insensitivity to pain with anhidrosis.

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder, characterized by loss of algesthesis and inability to sweat. CIPA is known to be caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene ( NTRK1). However, the details of NTRK1 mutations in Chinese CIPA patients remain unclear. In the present study, we recruited 36 CIPA patients from 34 unrelated families in mainland China. Blood samples from these patients and their available familial members were collected and subjected to genetic analysis. We identified 27 mutations in NTRK1 from this cohort, including 15 novel mutations. Interestingly, we discovered two forms of novel recurrent mutations: the first was a large intragenic deletion c.429-374_717 + 485del mediated by recombination between Alu elements, and the second was a deep intronic substitutions c.[851-798C > T;851-794C > G]. All probands were homozygotes or compound heterozygotes of these mutations. Current findings expand our knowledge about the mutation spectrum of NTRK1 in Chinese CIPA patients and provide more evidence for precise diagnosis of the clinically suspected patients with CIPA.

Magnetic resonance imaging of the spinal cord in the evaluation of 3 patients with sensory neuronopathies: Diagnostic assessment, indications of treatment response, and impact of autoimmunity: A case report.

RATIONALE: Sensory neuronopathy can be a devastating peripheral nervous system disorder. Profound loss in joint position is associated with sensory ataxia, and reflects degeneration of large-sized dorsal root ganglia. Prompt recognition of sensory neuronopathies may constitute a therapeutic window to intervene before there are irreversible deficits. However, nerve-conduction studies may be unrevealing early in the disease course. In such cases, the appearance of dorsal column lesions on spinal-cord MRI can help in the diagnosis. However, most studies have not defined whether such dorsal column lesions may occur within earlier as well as chronic stages of sensory neuronopathies, and whether serial MRI studies can be used to help assess treatment efficacy. In this case-series of three sensory neuronopathy patients, we report clinical characteristics, immunological markers, nerve-conduction and skin-biopsy studies, and neuroimaging features. PATIENT CONCERNS: All three patients presented with characteristic features of sensory neuronopathy with abnormal spinal-cord MRI studies. Radiographic findings included non-enhancing lesions in the dorsal columns that were longitudinally extensive (spanning ≥ 3 vertebral segments). DIAGNOSES: All patients had anti-Ro/SS-A and/or anti-La/SS-B antibodies, with patients one and two having Sjögren's syndrome. MRI findings were similar when performed in the earlier stages of a sensory neuronopathy (patient one, after four months) and chronic stages (patients two and three, after five and three years, respectively). INTERVENTIONS: Patient one was treated with rituximab combined with intravenous immunoglobulin therapy. OUTCOMES: Patient one was initially wheelchair-bound and had improved ambulation after treatment. In this patient, serial MRI studies revealed partial resolution of dorsal column lesions, associated with decreased sensory ataxia and improved nerve-conduction studies. LESSONS: In addition to vitamin B12 and copper deficiency, it is important to include sensory neuronopathies in the differential diagnosis of dorsal column lesions. MRI spinal-cord lesions have similar appearances in the earlier as well as chronic phases of a sensory neuronopathy, and therefore suggest that such dorsal column lesions may reflect inflammatory as well as a gliotic burden of injury. MRI may also be a useful longitudinal indicator of treatment response.

Novel NTRK1 mutations associated with congenital insensitivity to pain with anhidrosis verified by functional studies.

Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV, features loss of pain sensation, decreased or absent sweating (anhidrosis), recurrent episodes of unexplained fever, self-mutilating behavior, and variable mental retardation. Mutations in neurotrophic receptor tyrosine kinase 1 (NTRK1) have been reported to be associated with CIPA. We identified four novel NTRK1 mutations in six Korean patients from four unrelated families. Of the four mutations, we demonstrated using a splicing assay that IVS14+3A>T causes aberrant splicing of NTRK1 mRNA, leading to introduction of a premature termination codon. An NTRK1 autophosphorylation assay showed that c.1786G>A (p.Asp596Asn) abolished autophosphorylation of NTRK1. In addition, Western blotting showed that c.704C>G (p.Ser235*) and c.2350_2363del (p.Leu784Serfs*79) blunted NTRK1 expression to undetectable levels. The four novel NTRK1 mutations we report here will expand the repertoire of NTRK1 mutations in CIPA patients, and further our understanding of CIPA pathogenesis.

Old fractures in two patients with congenital insensitivity to pain with anhidrosis: radiological findings.

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disease that is characterized by anhidrosis, insensitivity to noxious stimuli, and mental retardation. Patients who suffer from CIPA easily sustain injuries due to pain insensitivity. Radiological findings in two CIPA patients revealed several old fractures of which the patients were unaware of previous injury. An early diagnosis of CIPA is important for the prevention and treatment of various complications. Our data indicate that radiological findings may provide important information for the diagnosis of CIPA.

Peripheral arthropathy in hereditary sensory and autonomic neuropathy types III and IV.

BACKGROUND: To determine the features of the underlying destructive arthropathy in the peripheral joints of children with hereditary sensory and autonomic neuropathy (HSAN) type III and to compare and contrast this to the arthropathy noted in HSAN type IV, as both groups experience decreased pain perception. METHODS: From a database of 547 patients with HSAN type III and 32 patients with HSAN type IV, we performed a retrospective chart review and radiographic analysis of all patients who presented with joint swelling and deformity. Underlying joint pathology was classified as either osteonecrosis or Charcot arthropathy. RESULTS: In the HSAN type III population, 44 (8%; 22 males and 22 females) of the 547 patients had clinical evidence of arthropathy. In 42 patients, 48 joints demonstrated radiographic evidence of osteonecrosis; 45 (94%) of the 48 joints with osteonecrosis occurred in the lower extremity. In each case of osteonecrosis of the knee (n = 19), isolated involvement of the lateral distal femoral condyle was seen consisting of varying sizes of posterolateral osteochondral fragmentation. In the 32 patients comprising the HSAN type IV population, 18 (56%) were found to have radiographic findings consistent with Charcot arthropathy in a total of 30 affected joints. One patient demonstrated Charcot arthropathy of the spine and subsequent progressive spondylolisthesis. Nine patients (12 joints) also demonstrated osteomyelitis. CONCLUSIONS: In patients with HSAN type III, osteonecrosis is the initial lesion preceding destructive arthropathy. Osteonecrosis and osteochondral fragmentation were always isolated at the lateral distal femoral condyle in the knee. This pathology may be amenable to surgical reconstruction and fixation to stabilize the knee and prevent further degeneration. Hereditary sensory and autonomic neuropathy type IV was most commonly associated with Charcot arthropathy or joint subluxation and dislocation. Late secondary changes at the articular surface may make radiographic distinction difficult. Charcot arthropathy affected both sides of the involved joint with evidence of collapse and fragmentation. With osteonecrosis, the articular process was found to be more focal.

Familial insensitivity to pain (HSAN V) and a mutation in the NGFB gene. A neurophysiological and pathological study.

We have studied a large Swedish family with a mutation in the nerve growth factor beta (NGFB) gene causing insensitivity to deep pain without anhidrosis (hereditary sensory and autonomic neuropathy, type V; HSAN V). Painfree joint destruction and fractures were common. Peripheral nerve conduction was normal, but temperature thresholds were increased. Sural nerve biopsies showed a moderate loss of A delta fibers and a severe reduction of C fibers. The three most severely affected cases were all born to consanguineous parents, and were homozygotes for the causal genetic mutation. Treatment of these patients is discussed.

Congenital insensitivity to pain with anhidrosis (CIPA): the spectrum of radiological findings.

BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) is an exceedingly rare, hereditary, sensory autonomic neuropathy (HSAN). AIM: To evaluate the various skeletal manifestations and cranial CT features in children affected by CIPA. MATERIALS AND METHODS: In the semidesert area of the Negev, the Bedouin tribes constitute a closed society where consanguineous marriages are the custom. This has resulted in a group of 20 children being affected by this rare autosomal recessive HSAN. The skeletal surveys and CT scans of these 20 Bedouin patients, 12 girls and 8 boys, ages ranging between 1 month and 8 years, were retrospectively analysed. Cranial CT scans were performed in ten children because of neonatal hypotonia and psychomotor retardation. The skeletal findings were classified as follows: fractures, joint deformities, joint dislocations, osteomyelitis, avascular necrosis and acro-osteolysis. RESULTS: All 20 patients had fractures of the extremities and acro-osteolysis of the fingers. Six had joint deformities. Three children had recurrent hip joint dislocations and another three had avascular necrosis. Ten patients presented with osteomyelitis of the limbs, acetabulum and scapula. The cranial CT scans disclosed mild brain volume loss with some ventriculomegaly. CONCLUSIONS: CIPA is a severe autosomal recessive condition that leads to self-mutilation early in life and to fractures, osteomyelitis and limb amputation in older children. Mental retardation is common. Death from hyperpyrexia occurs in almost 20 % of patients in the first 3 years of life.

Hereditary sensory and autonomic neuropathy type I (Thévenard's disease).

Radiographic and MR findings of two cases of hereditary sensory and autonomic neuropathy type I are reported. This rare disease has a non-specific radiographic and MR appearance. Differential diagnosis includes other types of hereditary and acquired sensory neuropathies affecting small myelinated and unmyelinated nerve fibers, as well as vascular abnormalities and lesions of the spinal cord.

The significance of x-ray examinations of limb musculature in neuromuscular diseases with special regard to childhood diseases.

On the basis of examinations performed on 29 children suffering from various muscular diseases, the authors give a detailed discussion of the application, indication and advantages of muscles x-rays in diagnosing neuromuscular diseases. With the help of x-rays of the musculature an inside view can be obtained in vivo, in a non-invasive manner, of structural changes in the muscles, and the progress of the disease can be followed up objectively. The method opens up new possibilities of diagnosis and promotes a more thorough knowledge of the pathological processes.

Autosomal recessive peripheral sensory neuropathy in 3 non-Ashkenazi Jewish families.

Three unrelated Oriental Jewish families with a total of eight subjects with progressive hereditary sensory neuropathy are reported. The parents were all unaffected and because of parental consanguinity in each of the three families it is postulated that this rare neurological disorder is transmitted in an autosomal recessive manner. In one family both parents showed an abnormal response to pain stimulation with normal motor and sensory nerve conduction velocity. This response may be an expression of the carrier state for this hereditary disease. Only five other families (non-Jewish) have been reported as having this form of peripheral hereditary sensory neuropathy. These observations suggest that one type, the progressive form, of peripheral hereditary sensory neuropathy may be more common in Oriental Jews.