Split-hand/foot malformation 3 resulting from microduplications in 10q24 region in five patients from India.

Split-hand/foot malformation (SHFM) is a genetically heterogeneous congenital limb reduction defect characterized by the deficiencies of central rays of the autopod. Tandem duplications at 10q24 locus account for approximately 20% of all SHFM cases. Here, we report five affected individuals from four unrelated Indian families with SHFM3 caused by microduplication of 10q24 locus showing varied clinical presentations. This report substantiates and extends the current understanding of this rare, multifaceted, and complex condition.

Electrodiagnostic findings in amyotrophic lateral sclerosis: Variation with region of onset and utility of thoracic paraspinal muscle examination.

INTRODUCTION/AIMS: Limited data exist regarding variation of electrodiagnostic (EDX) findings in amyotrophic lateral sclerosis (ALS) patients with different onset regions and specificity of thoracic paraspinal muscle (TPSP) examination for confirming a diagnosis of ALS. We aimed to demonstrate the variation of EDX features and characterize the utility of TPSP muscle examination in the electrodiagnosis of ALS. METHODS: This is a retrospective study of a large cohort of ALS patients who had a comprehensive EDX evaluation. RESULTS: The study included 448 patients; all fulfilled the Gold Coast criteria for ALS. The average age at the time of EDX study was 64 years, and 41.1% were women. The onset region was identified as follows: bulbar (N = 149), cervical (N = 127), lumbosacral (N = 162), and other (N = 10). In contrast to limb onset, bulbar-onset patients more frequently demonstrated a pattern of normal or near normal needle electromyography (EMG) (p < .0001) and less frequently had abnormalities on EMG of TPSP (p = .002). Clinical or EDX diagnosis of sensory polyneuropathy was present in 12.6% patients, more frequently in the lumbosacral onset subgroup (p < .03). EMG showed active denervation in 9.6% and chronic denervation in 59% of craniobulbar muscles examined, without observed difference among different onset regions. TPSP showed higher frequencies of active and chronic denervation in ALS than a group of patients with non-ALS neuromuscular disorders. DISCUSSION: EDX features may differ among ALS patients of different onset regions. TPSP EMG is highly useful in differentiating ALS from non-ALS neuromuscular disorders while the yield of craniobulbar muscles, especially for active denervation, is low.

Insights into phenotypic variability caused by GARS1 pathogenic variants.

BACKGROUND AND PURPOSE: Pathogenic variants of the glycyl-tRNA synthetase 1 (GARS1) gene have been described as a cause of Charcot-Marie-Tooth disease type 2D, motor axonal neuropathy with upper limb predominance (distal hereditary motor neuropathy [dHMN] type V), and infantile spinal muscular atrophy. METHODS: This cross-sectional, retrospective, observational study was carried out on 12 patients harboring the c.794C>T (p.Ser265Phe) missense pathogenic variant in GARS1. The patients' clinical data, nerve conduction studies, magnetic resonance imaging (MRI), and intraepidermal nerve fiber density in skin biopsies were reviewed. RESULTS: The mean age at onset was 9.5 years; the intrinsic hand muscles were affected before or at the same time as the distal leg musculature. The clinical examination revealed greater weakness of the distal muscles, with a more pronounced involvement of the thenar complex and the first dorsal interosseous in upper limbs. Electrophysiological studies were concordant with an exclusively motor axonal neuropathy. A pathologic split hand index was found in six patients. Muscle MRI showed predominant fatty infiltration and atrophy of the anterolateral and superficial posterior compartment of the legs. Most patients reported distal pinprick sensory loss. A reduced intraepidermal nerve fiber density was evident in skin biopsies from proximal and distal sites in nine patients. CONCLUSIONS: GARS1 variants may produce a dHMN phenotype with "split hand" and sensory disturbances, even when sensory nerve conduction studies are normal. This could be explained by a dysfunction of sensory neurons in the dorsal ganglion that is reflected as a reduction of dermal nerve endings in skin biopsies without a distal gradient.

Carcinogenesis caused by transcription-coupled DNA damage through GANP and other components of the TREX-2 complex.

Perturbation of genes is important for somatic hypermutation to increase antibody affinity during B-cell immunity; however, it may also promote carcinogenesis. Previous studies have revealed that transcription is an important process that can induce DNA damage and genomic instability. Transciption-export-2 (TREX-2) complex, which regulates messenger RNA (mRNA) nuclear export, has been studied in the budding yeast Saccharomyces cerevisiae; however, recent studies have started investigating the molecular function of the mammalian TREX-2 complex. The central molecule in the TREX-2 complex, that is, germinal center-associated nuclear protein (GANP), is closely associated with antibody affinity maturation as well as cancer etiology. In this review, we focus on carcinogenesis, lymphomagenesis, and teratomagenesis caused by transcription-coupled DNA damage through GANP and other components of the TREX-2 complex. We review the basic machinery of mRNA nuclear export and transcription-coupled DNA damage. We then briefly describe the immunological relationship between GANP and the affinity maturation of antibodies. Finally, we illustrate that the aberrant expression of the components of the TREX-2 complex, especially GANP, is associated with the etiology of various solid tumors, lymphomas, and testicular teratoma. These components serve as reliable predictors of cancer prognosis and response to chemotherapy.

Nerve conduction study on the split-hand plus index in Amyotrophic lateral sclerosis: correlations with lower motor neuron impairment.

INTRODUCTION: In the arms of patients with Amyotrophic lateral sclerosis (ALS) two peculiar patterns of dissociated muscular atrophy have been described: the split-hand sign (with predominant atrophy of the lateral aspect of the hand, compared to hypothenar eminence) and the split-hand-plus sign (SHPS), a predominant abductor pollicis brevis (ABP) atrophy with sparing of flexor pollicis longus (FPL). AIMS: In this case-control study, we evaluated the diagnostic utility of a neurophysiological indicator of SHPS and assessed its association with clinical features. METHODS: We prospectively studied 59 incident ALS patients, 61 patients with ALS-mimic disorders (OND) and 61 non-neurological controls (NNCs). ABP and FPL compound muscle action potentials (CMAP) amplitudes were obtained by supramaximal stimulation of median nerve at elbow. Split-hand plus index (SHPI) was calculated according to the formula: APB-CMAP/FPL-CMAP. RESULTS: SHPI was significantly lower in ALS compared to OND patients and NNCs (p < 0.0001). SHPI value < 1 was observed in 2% of NNCs and 9% of OND patients and demonstrated an accuracy of 71% in differentiating ALS from OND and an accuracy of 74% in differentiating ALS from NNC. SHPI was associated with higher LMN score, and higher disease severity as quantified by the ALSFRS-r. CONCLUSION: Our results indicate that SHPI is a reliable indicator to distinguish ALS patients from ONDs and NNCs. SHPI was significantly associated to the degree of lower motor neuron impairment but showed no association with upper motoneuron impairment.

When the diagnosis is in the patient's hand and in the neurologist's eye.

The objective of this study was to encompass current knowledge about pathophysiological mechanisms of those specific hand postures or deformities caused by central nervous system disorders. In the era of high-resolution neuroimaging and molecular biology, clinicians are progressively losing confidence with neurological examination. Careful hand observation is of key importance in order to differentiate neurological from non-neurological conditions, central from peripheral aetiologies, and organic from functional disorders. Localizing the potential anatomical site is essential to properly conduct subsequent exams. We provided a practical guide for clinicians to recognize hand patterns caused by central nervous system disorders, avoiding mimicking conditions, thus optimizing and prompting the diagnostic pathway.

Structural model of human PORCN illuminates disease-associated variants and drug-binding sites.

Wnt signaling is essential for normal development and is a therapeutic target in cancer. The enzyme PORCN, or porcupine, is a membrane-bound O-acyltransferase (MBOAT) that is required for the post-translational modification of all Wnts, adding an essential mono-unsaturated palmitoleic acid to a serine on the tip of Wnt hairpin 2. Inherited mutations in PORCN cause focal dermal hypoplasia, and therapeutic inhibition of PORCN slows the growth of Wnt-dependent cancers. Based on homology to mammalian MBOAT proteins, we developed and validated a structural model of human PORCN. The model accommodates palmitoleoyl-CoA and Wnt hairpin 2 in two tunnels in the conserved catalytic core, shedding light on the catalytic mechanism. The model predicts how previously uncharacterized human variants of uncertain significance can alter PORCN function. Drugs including ETC-159, IWP-L6 and LGK-974 dock in the PORCN catalytic site, providing insights into PORCN pharmacologic inhibition. This structural model enhances our mechanistic understanding of PORCN substrate recognition and catalysis, as well as the inhibition of its enzymatic activity, and can facilitate the development of improved inhibitors and the understanding of disease-relevant PORCN mutants. This article has an associated First Person interview with the joint first authors of the paper.

BHLHA9 homozygous duplication in a consanguineous family: A challenge for genetic counseling.

Split-hand/foot malformation (SHFM) with long-bone deficiency (SHFLD) is a rare condition characterized by SHFM associated with long-bone malformation usually involving the tibia. It includes three different types; SHFLD1 (MIM % 119,100), SHFLD2 (MIM % 610,685) and SHFLD3 (MIM # 612576). The latter was shown to be the most commonly reported with a duplication in the 17p13.1p13.3 locus that was narrowed down to the BHLHA9 gene. Here, we report a consanguineous Lebanese family with three members presenting with limb abnormalities including tibial hemimelia. One of these patients presented with additional bowing fibula and another with bilateral split hand. CGH array analysis followed by RQ-PCR allowed us to detect the first homozygous duplication on the short arm of chromosome 17p13.3 including the BHLHA9 gene and involved in SHFLD3. Interestingly, one patient with the homozygous duplicated region, carrying thus four BHLHA9 copies presented with long bone deficiency but no SHFM. The incomplete penetrance and the variable expressivity of the disease in this family as well as the presence of the BHLHA9 homozygous duplication rendered genetic counseling extremely challenging and preimplantation genetic diagnosis almost impossible.

Clinical and neurophysiological biomarkers of disease progression in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Rate of disease progression (ΔFS), measured as change in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and body mass index (BMI), are predictors of survival in amyotrophic lateral sclerosis (ALS). Our aim in this study was to assess the utility of these clinical biomarkers along with neurophysiological measures, such as the split hand index (SI), in monitoring disease progression. METHODS: Clinical trial data were collected from 107 patients recruited into the Tecfidera in ALS trial. The prognostic utility of clinical and neurophysiological measures, including ΔFS, BMI, SI, and neurophysiological index (NPI), were assessed cross-sectionally and longitudinally (40 weeks). The outcome measures of disease severity and progression included: (i) ALSFRS-R score; (ii) Medical Research Council (MRC) score; and (iii) forced vital capacity and sniff nasal inspiratory pressure. RESULTS: Fast-progressor ALS patients (ΔFS ≥1.1) exhibited significantly lower ALSFRS-R and total MRC scores at baseline. A baseline ΔFS score ≥1.1 was associated with a greater reduction in ALSFRS-R (P = .002) and MRC (P = .002) scores over 40 weeks. Baseline BMI <25 was also associated with faster reduction of ALSFRS-R and MRC scores. SI and NPI were associated with disease severity at baseline, but not with subsequent rate of disease progression. DISCUSSION: Implementation of the assessed clinical and neurophysiological biomarkers may assist in patient management and stratification into clinical trials.

Microduplication of BTRC detected in a Chinese family with split hand/foot malformation type 3.

Split hand/foot malformation (SHFM) is a clinically heterogeneous genetic disorder, which is mainly characterized by median clefts of the hand/feet due to the absence of the central digital rays. Several subgroups of SHFM have been identified, including SHFM1 to SHFM6. SHFM3 is an autosomal dominant disease, which has been identified to associate with a 500 kb microduplication at 10q24. The duplication involved several genes, including LBX1, BTRC, POLL, FBXW4, and so forth. In the study, using trio clinical exome sequencing, a 120 kb microduplication containing only BTRC were identified in a Chinese family affected with SHFM3. Further confirmation was performed using qRT-PCR assay, which showed that the 120 kb duplication was co-segregated with SHFM phenotypes in the family. It is the smallest duplication which has ever been reported relating to SHFM3. Furthermore, the transcription levels of BTRC mRNA in lymphocyte of the proband was significantly higher than that in the healthy control. The study provided evidence for the limb malformation caused by abnormal BTRC expression, and suggested that next generation sequencing could provide more precise diagnosis to SHFM3 patients.

The senile hand: Age effects on intrinsic hand muscle CMAP amplitudes influence split-hand index calculations.

INTRODUCTION/AIMS: Age can affect hand muscles non-uniformly. We investigated the influence of age on the compound muscle action potential (CMAP) amplitude of the hand muscles and the derived split-hand index (SHI). METHODS: We studied 244 subjects investigated for suspected myasthenia gravis but without neuromuscular disorders. Abductor pollicis brevis (APB), first dorsal interosseous (FDI), and abductor digiti minimi (ADM) CMAPs were obtained by supramaximal stimulation at the wrist, recording with surface electrodes while checking the best recording site. We applied Tukey's HSD and Kruskal-Wallis one-way analysis of variance for comparing age groups defined by median and interquantile ranges (IQRs). Spearman's rank correlation coefficient and linear regression were used for testing age-dependence of measurements. RESULTS: Median age was 61.5 y (first IQR, 44.5; third IQR, 72.0; range 18-89). Age and neurophysiological measurements were similar between genders. APBCMAP , FDICMAP , ADMCMAP , and SHI were correlated with age (P < .001). Median and cutoff values were significantly different between age groups. APBCMAP , FDICMAP , and ADMCMAP decreased by 0.8/0.7/0.3 mV/y, respectively, and SHI decreased 0.15/y. DISCUSSION: The CMAP amplitudes of hand muscles and derived SHI were strongly age-dependent, although this effect was less in ADM. This represents a physiological phenomenon. Future studies using the SHI should consider age effects.

From the Luttrell Psalter to the Lobster Boy: Split hand and foot awaken many facets of human nature.

A marginal illustration of a non-ambulatory child in the 14th Century Luttrell Psalter is the earliest currently identifiable image of an individual with Split Hand Split Foot with Long Bone Deficiency (SHFLD). Changes in portrayal of SHFLD over the centuries reflect changes in social perception of disabilities from pious sympathy to scientific curiosity and unfortunately also morbid fascination. Hopefully understanding of the past attitudes toward split hand and foot as reflected in art can help in moving toward acceptance of individuals with this highly visible malformation.

Clinical and electrophysiological examination of pinch strength in patients with amyotrophic lateral sclerosis.

BACKGROUND: The split-hand concept has highlighted the preferential wasting of the thenar side of the hand in amyotrophic lateral sclerosis (ALS). Our objective is to re-explore pinch grip strength to assess whether it has the potential to be a practical biomarker of ALS. METHODS: We measured different pinch grip strengths (thumb, index, and fifth) using a pinch gauge from both hands of 54 ALS patients and correlated this with the Medical Research Council (MRC) score, the upper-limb component of the revised ALS Functional Rating Scale - Revised (ALSFRS-R) score, and compound muscle action potentials (CMAPs) that comprise the split-hand index. RESULTS: Pinch grip strength using any of the three fingers showed a positive correlation with its corresponding CMAP, MRC grading, and upper-limb ALSFRS-R score. The thumb pinch showed the strongest correlation with the split-hand index and MRC grading. CONCLUSIONS: Pinch grip strength test using a simple gauge deserves further study as a potentially practical biomarker of ALS.

Reproducibility of motor unit number index and MScanFit motor unit number estimation across intrinsic hand muscles.

INTRODUCTION: We sought to evaluate the reproducibility of the motor unit number index (MUNIX) and MScanFit motor unit number estimation (MScan) when recording was performed over intrinsic hand muscles. METHODS: The compound muscle action potential (CMAP) amplitude, MUNIX, and MScan were measured from the abductor pollicis brevis (APB), first dorsal interosseous (FDI), and abductor digit minimi (ADM) muscles from 15 healthy volunteers on three different occasions. RESULTS: The reproducibility of CMAP amplitudes was excellent, with intraclass correlation coefficients (ICC) of 0.86 (APB), 0.90 (FDI), and 0.96 (ADM). Motor unit number index (ICCAPB 0.73, ICCFDI 0.85, ICCADM 0.85) and MScan (ICCAPB 0.86, ICCFDI 0.83, ICCADM 0.81) were highly reproducible across the three muscles. There were no significant correlations between MUNIX and MScan coefficients of variation (CV) and CMAP amplitude CVs. DISCUSSION: Reproducibility of MUNIX and MScan was not significantly different across the intrinsic hand muscles and was independent of CMAP amplitude variability.

Split hand/foot malformation with long bone deficiency associated with BHLHA9 gene duplication: a case report and review of literature.

BACKGROUND: Split hand/foot malformation (SHFM) is a group of congenital skeletal disorders which may occur either as an isolated abnormality or in syndromic forms with extra-limb manifestations. Chromosomal micro-duplication or micro-triplication involving 17p13.3 region has been described as the most common cause of split hand/foot malformation with long bone deficiency (SHFLD) in several different Caucasian and Asian populations. Gene dosage effect of the extra copies of BHLHA9 gene at this locus has been implicated in the pathogenesis of SHFLD. CASE PRESENTATION: The proband was a female child born to non-consanguineous parents. She was referred for genetic evaluation of bilateral asymmetric ectrodactyly involving both hands and right foot along with right tibial hemimelia. The right foot had fixed clubfoot deformity with only 2 toes. The mother had bilateral ectrodactyly involving both hands, but the rest of the upper limbs and both lower limbs were normal. Neither of them had any other congenital malformations or neurodevelopmental abnormalities. Genetic testing for rearrangement of BHLHA9 gene by quantitative polymerase chain reaction confirmed the duplication of the BHLHA9 gene in both the proband and the mother. CONCLUSIONS: We report the first Sri Lankan family with genetic diagnosis of BHLHA9 duplication causing SHFLD. This report along with the previously reported cases corroborate the possible etiopathogenic role of BHLHA9 gene dosage imbalances in SHFM and SHFLD across different populations.

WNT10B variants in split hand/foot malformation: Report of three novel families and review of the literature.

Split-hand/foot malformation (SHFM) is a genetically heterogeneous congenital limb malformation typically limited to a defect of the central rays of the autopod, presenting as a median cleft of hands and feet. It can be associated with long bone deficiency or included in more complex syndromes. Among the numerous genetic causes, WNT10B homozygous variants have been recently identified in consanguineous families, but remain still rarely described (SHFM6; MIM225300). We report on three novel SHFM families harboring WNT10B variants and review the literature, allowing us to highlight some clinical findings. The feet are more severely affected than the hands and there is a frequent asymmetry without obvious side-bias. Syndactyly of third-fourth fingers was a frequent finding (62%). Polydactyly, which was classically described in SHFM6, was only present in 27% of patients. No genotype-phenotype correlation is delineated but heterozygous individuals might have mild features of SHFM, suggesting a dose-effect of the WNT10B loss-of-function.

Parameters derived from compound muscle action potential scan for discriminating amyotrophic lateral sclerosis-related denervation.

INTRODUCTION: The objective of this study was to determine compound muscle action potential (CMAP) scan parameters and MScanFit motor unit number estimation (MUNE) in patients with amyotrophic lateral sclerosis (ALS) and to compare the results in the abductor pollicis brevis (APB) to those in the abductor digiti minimi (ADM). METHODS: CMAP scans were recorded from the APB and ADM in 35 patients with ALS and 21 controls. MScanFit MUNE, neurophysiological index (NI), step%, returner%, and D50 were calculated. RESULTS: CMAP scan parameters including the returner%, MScanFit MUNE, and NI can distinguish ALS with high sensitivity and specificity. The electrophysiological parameters, with the exception of D50 (the number of largest consecutive differences of recorded responses generating 50% of maximum CMAP), showed more pronounced changes in the APB than in the ADM, even though most of the patients had normal APB/ADM amplitude ratios. DISCUSSION: CMAP scan parameters and MScanFit MUNE can be used in the evaluation of denervation and reinnervation and may herald the "split hand" in ALS.

Split Hand Foot Malformation Syndrome: A Novel Heterozygous FGFR1 Mutation Detected by Next Generation Sequencing.

BACKGROUND: Split-hand/foot malformation syndrome is a rare, clinically and genetically het-erogeneous group of limb malformations characterized by absence/hypoplasia and/or median cleft of hands and/or feet. It may occur as an isolated abnormality or it may be associated with a genetic syn-drome. CASE REPORT: In the present case, isolated split-hand/split-foot malformation was diagnosed by prenatal ultrasound at 24 weeks in a male singleton fetus, with deep median cleft of the right hand, syndactyly and hypoplasia of phalanges in both hands, and oligodactyly of the right foot. During consultation, the father of the fetus revealed that he also had an isolated right foot dysplasia. The parents chose elective termination and autopsy confirmed prenatal ultrasound findings. Genetic testing of the aborted fetus with QF-PCR analysis for common aneuploidies and array comparative genomic hybridization (aCGH) showed a male genomic pattern, without aneuploidies or chromosomal imbalances. Further investigation with next generation sequencing of 49 clinically relevant genes revealed a novel heterozygous FGFR1 mutation c.787_789del (p.Ala263del) in the fetus; the father was heterozygous to the same mutation. CONCLUSION: A novel heterozygous FGFR1 mutation causing split-hand/foot malformation syndrome is reported. Accurate genetic diagnosis allowed detailed counseling to be provided to the couple, including the underlying cause, recurrence risks, and detailed management plan with preimplantation genetic diag-nosis for future pregnancies.

WNT10B mutations associated with isolated dental anomalies.

Isolated hypodontia is the most common human malformation. It is caused by heterozygous variants in various genes, with heterozygous WNT10A variants being the most common cause. WNT10A and WNT10B are paralogs that likely evolved from a common ancestral gene after its duplication. Recently, an association of WNT10B variants with oligodontia (severe tooth agenesis) has been reported. We performed mutational analysis in our cohort of 256 unrelated Thai families with various kinds of isolated dental anomalies. In 7 families afflicted with dental anomalies we detected 4 heterozygous missense variants in WNT10B. We performed whole exome sequencing in the patients who had WNT10B mutations and found no mutations in other known hypodontia-associated genes, including WNT10A, MSX1, PAX9, EDA, AXIN2, EDAR, EDARADD, LPR6, TFAP2B, LPR6, NEMO, KRT17, and GREM2. Our findings indicate that the variants c.475G>C [p.(Ala159Pro)], found in 4 families, and c.1052G>A [p.(Arg351His)], found in 1 family, are most probably causative. They also show that WNT10B variants are associated not only with oligodontia and isolated tooth agenesis, but also with microdontia, short tooth roots, dental pulp stones, and taurodontism.

Spinal excitability changes do not influence the mechanisms of split-hand syndrome in amyotrophic lateral sclerosis.

INTRODUCTION: We studied spinal excitability and its relation to motor unit action potential (MUAP) changes in the thenar and hypothenar muscles in patients with amyotrophic lateral sclerosis (ALS). METHODS: Quantitative MUAP and peak ratio interference analyses were performed, and cutaneous silent period (CutSP) was measured in the abductor digiti minimi (ADM) and first dorsal interosseous (FDI) muscles of patients with ALS and controls. RESULTS: Patients with ALS revealed more prominently increased duration (P = 0.002), number of phases (P = 0.02), size index (P = 0.02), and thickness (P = 0.02) in ADM than in FDI. The number of small segments was significantly decreased in ADM (P = 0.036) compared with controls. CutSP latency was prolonged in both ADM and FDI in ALS (P < 0.05). DISCUSSION: Although the reinnervation capacity was notably higher in the ADM of patients with ALS, the lack of a significant difference in CutSP measurements between ADM and FDI argues against spinal excitability changes in the development of split-hand syndrome. Muscle Nerve 58: 503-508, 2018.