The genotype-phenotype landscape of familial amyotrophic lateral sclerosis in Australia.

Amyotrophic lateral sclerosis (ALS) is a clinically and genetically heterogeneous fatal neurodegenerative disease. Around 10% of ALS cases are hereditary. ALS gene discoveries have provided most of our understanding of disease pathogenesis. We aimed to describe the genetic landscape of ALS in Australia by assessing 1013 Australian ALS patients for known ALS mutations by direct sequencing, whole exome sequencing or repeat primed polymerase chain reaction. Age of disease onset and disease duration were used for genotype-phenotype correlations. We report 60.8% of Australian ALS families in this cohort harbour a known ALS mutation. Hexanucleotide repeat expansions in C9orf72 accounted for 40.6% of families and 2.9% of sporadic patients. We also report ALS families with mutations in SOD1 (13.7%), FUS (2.4%), TARDBP (1.9%), UBQLN2 (.9%), OPTN (.5%), TBK1 (.5%) and CCNF (.5%). We present genotype-phenotype correlations between these genes as well as between gene mutations. Notably, C9orf72 hexanucleotide repeat expansion positive patients experienced significantly later disease onset than ALS mutation patients. Among SOD1 families, p.I114T positive patients had significantly later onset and longer survival. Our report highlights a unique spectrum of ALS gene frequencies among patients from the Australian population, and further, provides correlations between specific ALS mutations with disease onset and/or duration.

Mutation analysis of genes within the dynactin complex in a cohort of hereditary peripheral neuropathies.

The cytoplasmic dynein-dynactin genes are attractive candidates for neurodegenerative disorders given their functional role in retrograde transport along neurons. The cytoplasmic dynein heavy chain (DYNC1H1) gene has been implicated in various neurodegenerative disorders, and dynactin 1 (DCTN1) genes have been implicated in a wide spectrum of disorders including motor neuron disease, Parkinson's disease, spinobulbar muscular atrophy and hereditary spastic paraplegia. However, the involvement of other dynactin genes with inherited peripheral neuropathies (IPN) namely, hereditary sensory neuropathy, hereditary motor neuropathy and Charcot-Marie-Tooth disease is under reported. We screened eight genes; DCTN1-6 and ACTR1A and ACTR1B in 136 IPN patients using whole-exome sequencing and high-resolution melt (HRM) analysis. Eight non-synonymous variants (including one novel variant) and three synonymous variants were identified. Four variants have been reported previously in other studies, however segregation analysis within family members excluded them from causing IPN in these families. No variants of disease significance were identified in this study suggesting the dynactin genes are unlikely to be a common cause of IPNs. However, with the ease of querying gene variants from exome data, these genes remain worthwhile candidates to assess unsolved IPN families for variants that may affect the function of the proteins.

Transanal rectal resection: an initial experience of 20 cases.

AIM: Low anterior resection (LAR) can present a formidable surgical challenge, particularly for tumours located in the distal third of the rectum. Transanal total mesorectal excision (taTME) aims to overcome some of these difficulties. We report our initial experience with this technique. METHOD: From June 2013 to September 2014, 20 selected patients underwent transanal rectal resection for various malignant and benign low rectal pathologies. All patients with rectal cancer were discussed at a multidisciplinary team meeting. Data were entered into a prospective managed international database. RESULTS: Of the 20 patients (14 male), seventeen (85%) had rectal cancer lying at a median distance of 2 cm (range 0-7) from the anorectal junction. The operations performed included LAR (16). Abdominoperineal excision (2) and completion proctectomy (2), all of which were performed by a minimally invasive approach with three conversions. The mean operation time was 315.3 min. There were six postoperative complications of which two (10%) were Clavien-Dindo Grade IIIb (pelvic haematoma and a late contained anastomotic leakage). The median length of stay was 7 days. The TME specimen was intact in 94.1% of cancer cases. The mean number of harvested lymph nodes was 23.2. There was only one positive circumferential resection margin (tumour deposit; R1 rate 5.9%). One patient developed a distant recurrence (median follow-up 10 months, range 6-21). CONCLUSION: TaTME was safe in this small series of patients. It is especially attractive in patients with a narrow and irradiated pelvis and a tumour in the lower third of the rectum. TaTME is technically demanding, but the good outcomes should prompt randomized studies and prospective registration of all taTME cases in an international registry.

Laparoscopic rectopexy is feasible and safe in the emergency admission setting.

AIM: External rectal prolapse may require emergency admission in the elderly and comorbid population. We report the safety and efficacy of laparoscopic ventral rectopexy in patients having an emergency admission with external rectal prolapse. METHOD: A retrospective analysis was performed of a prospective database of all rectopexies performed from 2006. Outcome and follow-up data were assessed. RESULTS: Of 812 rectopexies performed, 28 were included for analysis. The mean length of hospital stay was 13.0 days. All operations were completed successfully and without intra-operative complications. Four patients developed a postoperative complication. Two patients developed a recurrence of prolapse. CONCLUSION: Laparoscopic correction of rectal prolapse following emergency admission is both feasible and safe. It can be considered for both recurring cases and cases with multiple comorbidities.

Contribution of surgical specialization to improved colorectal cancer survival.

BACKGROUND: Reorganization of colorectal cancer services has led to surgery being increasingly, but not exclusively, delivered by specialist surgeons. Outcomes from colorectal cancer surgery have improved, but the exact determinants remain unclear. This study explored the determinants of outcome after colorectal cancer surgery over time. METHODS: Postoperative mortality (within 30 days of surgery) and 5-year relative survival rates for patients in the West of Scotland undergoing surgery for colorectal cancer between 1991 and 1994 were compared with rates for those having surgery between 2001 and 2004. RESULTS: The 1823 patients who had surgery in 2001-2004 were more likely to have had stage I or III tumours, and to have undergone surgery with curative intent than the 1715 patients operated on in 1991-1994. The proportion of patients presenting electively who received surgery by a specialist surgeon increased over time (from 14·9 to 72·8 per cent; P < 0·001). Postoperative mortality increased among patients treated by non-specialists over time (from 7·4 to 10·3 per cent; P = 0·026). Non-specialist surgery was associated with an increased risk of postoperative death (adjusted odds ratio 1·72, 95 per cent confidence interval (c.i.) 1·17 to 2·55; P = 0·006) compared with specialist surgery. The 5-year relative survival rate increased over time and was higher among those treated by specialist compared with non-specialist surgeons (62·1 versus 53·0 per cent; P < 0·001). Compared with the earlier period, the adjusted relative excess risk ratio for the later period was 0·69 (95 per cent c.i. 0·61 to 0·79; P < 0·001). Increased surgical specialization accounted for 18·9 per cent of the observed survival improvement. CONCLUSION: Increased surgical specialization contributed significantly to the observed improvement in longer-term survival following colorectal cancer surgery.

Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I.

Hereditary sensory neuropathy type I (HSN1) is the most common hereditary disorder of peripheral sensory neurons. HSN1 is an autosomal dominant progressive degeneration of dorsal root ganglia and motor neurons with onset in the second or third decades. Initial symptoms are sensory loss in the feet followed by distal muscle wasting and weakness. Loss of pain sensation leads to chronic skin ulcers and distal amputations. The HSN1 locus has been mapped to chromosome 9q22.1-22.3 (refs. 3,4). Here we map the gene SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, to this locus. Mutation screening revealed 3 different missense mutations resulting in changes to 2 amino acids in all affected members of 11 HSN1 families. We found two mutations to be located in exon 5 (C133Y and C133W) and one mutation to be located in exon 6 of SPTLC1 (V144D). All families showing definite or probable linkage to chromosome 9 had mutations in these two exons. These mutations are associated with increased de novo glucosyl ceramide synthesis in lymphoblast cell lines in affected individuals. Increased de novo ceramide synthesis triggers apoptosis and is associated with massive cell death during neural tube closure, raising the possibility that neural degeneration in HSN1 is due to ceramide-induced apoptotic cell death.

The gene for hereditary sensory neuropathy type I (HSN-I) maps to chromosome 9q22.1-q22.3.

Hereditary sensory neuropathy type I (HSN-I, also known as hereditary sensory and autonomic neuropathy type I (HSAN-I), or hereditary sensory radicular neuropathy) is an autosomal dominant disorder that is the most common of a group of degenerative disorders of sensory neurons. HSN-I was initially recognized as a disease that produced mutilating ulceration leading to amputation of digits (Fig. 1). It was given names such as familial ulcers with mutilating lesions of the extremities and perforating ulcers with osseous atrophy. The disease involves a progressive degeneration of dorsal root ganglion and motor neurons, leading to distal sensory loss and later distal muscle wasting and weakness and variable neural deafness. Sensory deficits include loss of all modalities, particularly loss of sensation to pain and temperature. Skin injuries may lead to chronic skin ulcers, osteomyelitis, and extrusion of bone fragments, especially the metatarsals. Onset of symptoms is in the second or later decades. We undertook a genome screen using linkage analysis in four Australian HSN-I kindreds. We now show that the HSN1 gene maps to an 8-centiMorgan (cM) region flanked by D9S318 and D9S176 on chromosome 9q22.1-q22.3. Multipoint linkage analysis suggests a most likely location at D9S287, within a 4.9-cM confidence interval.

De novo mutation of the myelin P0 gene in Dejerine-Sottas disease (hereditary motor and sensory neuropathy type III).

We have investigated the myelin P0 gene on chromosome 1 as a candidate gene in two sporadic cases with Dejerine-Sottas disease or hereditary motor and sensory neuropathy (HMSN) type III. We found different mutations, a cysteine substitution for serine 63 in the extracellular domain and an arginine substitution for glycine 167 in the transmembrane domain. The patients were genetically heterozygous for the normal allele and the mutant allele, which was absent in their parents and in one hundred unrelated, healthy controls. The results strongly suggest that a de novo dominant mutation of the P0 gene is responsible for at least some sporadic cases of Dejerine-Sottas disease.

A frame shift mutation in the PMP22 gene in hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (HNPP) has been a associated with a deletion of 1.5 megabases of chromosome 17p. One of four biopsy proven HNPP families that we have studied did not possess this deletion. As the deleted DNA region includes the coding region for a peripheral myelin gene (PMP22), we used single strand conformation analysis to examine this gene for mutations in the non-deleted HNPP family. An abnormal fragment in exon 1 was identified, and sequencing revealed a two base pair deletion in all affected family members. The deletion results in a frame shift, providing strong evidence that this gene has an important role in the pathogenesis of the disease.

Quality of care in rectal cancer surgery. Exploring influencing factors in the West of Scotland.

AIM: To assess variability in the proportions of types of major resection for rectal cancer throughout the west of Scotland (WoS) and ascertain factors explaining the variability. METHOD: Retrospective cohort study of a regional population clinical audit database. This was linked to cancer registrations and death certificates in order that outcome analyses could be derived. Univariate and multivariate binary logistic regression analyses were used to explore determinants of survival. RESULTS: A total of 1574 patients met the inclusion criteria. The age range was from 22 to 97 years. The mean age was 67, median age 68 and the standard deviation was 11.5. The majority of patients (61%) were male. Unlike previous series, male patients and those with poorer socioeconomic circumstances (SEC) were no more likely to receive an abdominoperineal excision (APE) procedure for rectal cancer. CONCLUSION: Variation exists in the west of Scotland regarding surgical treatment for rectal cancer. We found no difference in the type of procedure offered according to sex, intent of operation or socioeconomic circumstances with reference to APE and anterior resection (AR) for rectal cancer. We conclude therefore that our region provides an equitable service on grounds of sex and SEC. This demonstrates that an equitable surgical service has been provided for those suffering from rectal cancer. Circumferential margin positivity was four times more likely in an APE than an AR for rectal cancer. This is not explained by age, stage, sex, socioeconomic circumstances (SEC), volume of surgery, intent of operation, type of admission or year of incidence.

Mechanical bowel preparation does not influence outcomes following colonic cancer resection.

BACKGROUND: Meta-analyses have indicated that preoperative mechanical bowel preparation (MBP) confers no clear benefit and may indeed be harmful for patients with colorectal cancer. The effects of bowel preparation on longer-term outcomes have not been reported. The aim was to compare long-term survival and surgical complications in patients who did or did not receive MBP before surgery for colonic cancer. METHODS: This was a retrospective cohort study of all patients undergoing potentially curative surgery for colonic cancer after routine hospital admission in the West of Scotland between January 2000 and December 2005. Clinical audit data were linked to cancer registrations and death certificates. Kaplan-Meier and Cox proportional hazards models were used to explore determinants of survival. RESULTS: A total of 1730 patients underwent potentially curative surgery for colonic cancer, of whom 886 (51·2 per cent) were men. The mean(s.d.) age was 69·7(10·6) years. Some 1460 patients (84·4 per cent) received MBP. Median follow-up was 3·5 (range 0·1-6·7) years. There were no statistically significant differences in 30-day postoperative complication rates between groups. The unadjusted hazard ratio (HR) for death from all causes for patients treated with MBP (versus no MBP) was 0·72 (95 per cent confidence interval 0·57 to 0·91). Multivariable analysis with adjustment for age, sex, socioeconomic circumstances, disease stage and presentation for surgery showed that MBP had no independent effect on all-cause mortality (HR 0·85, 0·67 to 1·10). CONCLUSION: Neither postoperative complications nor long-term survival are improved by MBP before colonic cancer surgery.

Cortical excitability in hereditary motor neuronopathy with pyramidal signs: comparison with ALS.

BACKGROUND: Distal hereditary motor neuronopathy with pyramidal features (dHMNP) is a hereditary neurodegenerative disorder characterised by the presence of upper and lower motor neuron signs. The pathophysiological mechanisms underlying these clinical findings remain elusive. Given that cortical hyperexcitability appears to underlie neurodegeneration in amyotrophic lateral sclerosis (ALS), a disorder that may clinically resemble dHMNP, the present study applied novel cortical excitability studies to further investigate the pathophysiological mechanisms in dHMNP. METHODS: Threshold tracking transcranial magnetic stimulation (TMS) studies were undertaken using a 90 mm circular coil. Peripheral nerve excitability was performed by stimulating the median nerve at the wrist, with recording made over the abductor pollicis brevis muscle. Studies were undertaken in six dHMNP and 52 ALS patients, and compared with 55 normal controls. RESULTS: Central motor conduction time (CMCT) was significantly prolonged in dHMNP (dHMNP 7.7 (SEM 0.7) ms; ALS 4.9 (0.3) ms; controls 5.1 (0.2) ms, p<0.01). Short interval intacortical inhibition (SICI) was significantly reduced in ALS patients (0.8 (0.8)%) when compared with dHMNP (6.4 (0.7)%, p<0.0001) and controls (8.6 (1.1)%, p<0.0001). Reduction in SICI was accompanied by significant increases in the magnetic stimulus-response curve gradient and intracortical facilitation, and reduction in cortical silent period duration in ALS, while all these parameters of cortical excitability were normal in dHMNP. CONCLUSIONS: The present study has established a prolonged CMCT and normal cortical excitability in dHMNP, thereby providing further support for the hypothesis that cortical hyperexcitability underlies neurodegeneration in ALS.

A novel TARDBP mutation in an Australian amyotrophic lateral sclerosis kindred.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that causes loss of motor neurons. A pathological hallmark of ALS is the presence of ubiquitinated TAR DNA binding protein (TDP-43) inclusions in the cytoplasm of affected cells. Rare pathogenic mutations within the gene TARDBP that encode TDP-43 were recently reported in ALS but their functional consequences are unknown. To further investigate the pathogenic role of TDP-43 in ALS, a mutation analysis of TARDBP was performed in an Australian cohort of 74 sporadic and 30 familial ALS cases. A novel familial ALS mutation in TDP-43 was identified that substitutes a highly conserved residue (G294V) and is predicted to disrupt the glycine rich domain in the C terminus, a region that plays a role in RNA binding and is required for the exon skipping activity of TDP-43.

Quantitative muscle ultrasound as a biomarker in Charcot-Marie-Tooth neuropathy.

OBJECTIVE: The utility of quantitative muscle ultrasound as a marker of disease severity in Charcot-Marie-Tooth (CMT) disease subtypes was investigated. METHODS: Muscle ultrasound was prospectively performed on 252 individual muscles from 21 CMT patients (9 CMT1A, 8 CMTX1, 4 CMT2A) and compared to 120 muscles from 10 age and gender-matched controls. Muscle ultrasound recorded echogenicity and thickness in representative muscles including first dorsal interosseus (FDI) and tibialis anterior (TA). RESULTS: Muscle volume of FDI and thickness of TA correlated with MRC strength. Muscle echogenicity was significantly increased in FDI (65.05 vs 47.09; p<0.0001) and TA (89.45 vs 66.30; p<0.0001) of CMT patients. In TA, there was significantly higher muscle thickness (23 vs 18 vs 16mm; p<0.0001) and lower muscle echogenicity (80 vs 95 vs 108; p<0.0001) in CMT1A compared to CMTX1 and CMT2A. This corresponded to disease severity based on muscle strength (MRC grading CMT1A vs CMTX1 vs CMT2A: 59 vs 48 vs 44; p=0.002). CONCLUSION: In CMT, quantitative muscle ultrasound of FDI and TA is a useful marker of disease severity. SIGNIFICANCE: The current findings suggest that quantitative muscle ultrasound has potential as a surrogate marker of disease progression in future interventional trials in CMT.

Augmenting the decision making process in acute appendicitis: A retrospective cohort study.

INTRODUCTION: Acute appendicitis is a common surgical diagnosis. We investigated the use of blood markers (WCC, CRP and serum bilirubin) and diagnostic imaging (USS and CT scan) to arrive at this diagnosis, as well as the surgical approach used for appendicectomy. METHODS: This was a retrospective analysis of consecutive patients undergoing appendicectomy in seven hospitals within GG&C Health Board during a 6 month study period. Data were collected from electronic patient records. Sensitivity and specificity of each investigation for diagnosing acute appendicitis was calculated. RESULTS: 363 patients were included. Appendicectomy was performed open in 53%, laparoscopically in 43% and converted in 4%. Diagnostic imaging was used in 38%. The overall negative appendicectomy rate was 15% (18% when no imaging was used, 23% when USS was used and 1% when CT scanning was used). Elevated bilirubin had a sensitivity of 0.44 and a specificity of 0.84 for detecting acute appendicitis. Sensitivity and specificity for elevated WCC were 0.78 and 0.55, and for elevated CRP were 0.81 and 0.59, respectively. The specificity of bilirubin for diagnosing perforated appendicitis was 0.63. DISCUSSION: WCC and CRP were sensitive blood markers in acute appendicitis, whereas serum bilirubin was more specific. Diagnostic imaging with a CT scan was very effective at reducing the rate of negative appendicectomy, but USS was not. CONCLUSION: Serum bilirubin has utility in diagnosing acute appendicitis, irrespective of whether perforation has occurred. CT scanning should be considered the first line imaging modality for investigation of acute appendicitis if diagnosis is in doubt.

A national trainee-led audit of inguinal hernia repair in Scotland.

PURPOSE: This audit assessed inguinal hernia surgery in Scotland and measured compliance with British Hernia Society Guidelines (2013), specifically regarding management of bilateral and recurrent inguinal hernias. It also assessed the feasibility of a national trainee-led audit, evaluated regional variations in practise and gauged operative exposure of trainees. METHODS: A prospective audit of adult inguinal hernia repairs across every region in Scotland (30 hospitals in 14 NHS boards) over 2-weeks was co-ordinated by the Scottish Surgical Research Group (SSRG). RESULTS: 235 patients (223 male, median age 61) were identified and 96 % of cases were elective. Anaesthesia was 91 % general, 5 % spinal and 3 % local. Prophylactic antibiotics were administered in 18 %. Laparoscopic repair was used in 33 % (30 % trainee-performed). Open repair was used in 67 % (42 % trainee-performed). Elective primary bilateral hernia repairs were laparoscopic in 97 % while guideline compliance for an elective recurrence was 77 %. For elective primary unilateral hernias, the use of laparoscopic repair varied significantly by region (South East 43 %, North 14 %, East 7 % and West 6 %, p < 0.001) as did repair under local anaesthesia for open cases (North 21 %, South East 4 %, West 2 % and East 0 %, p = 0.001). Trainees independently performed 9 % of procedures. There were no significant differences in trainee or unsupervised trainee operator rates between laparoscopic and open cases. Mean hospital stay was 0.7-days with day case surgery performed in 69 %. CONCLUSIONS: This trainee-lead audit provides a contemporary view of inguinal hernia surgery in Scotland. Increased compliance on recurrent cases appears indicated. National re-audit could ensure improved adherence and would be feasible through the SSRG.

Phenotypic expression of benign familial neonatal convulsions linked to chromosome 20.

OBJECTIVES: To determine whether the syndrome of benign familial neonatal convulsions in a large family was linked to markers on chromosome 20q and to study the seizure patterns in affected individuals. DESIGN: A clinical and molecular biologic study of a single large family in which the probands were identical twins with benign familial neonatal convulsions. PATIENTS: Thirteen living affected family members and 27 living unaffected family members were evaluated. RESULTS: Multipoint linkage analysis with use of the chromosome 20q markers CMM6 and RMR6 gave a maximum lod score of 3.13 at theta = 0.063, indicating linkage in this family. Of the 13 affected members, 10 had known neonatal seizures. Four subjects had febrile seizures, of whom only two had known neonatal seizures. Two members had afebrile seizures later, one of whom had not previously suffered neonatal or febrile seizures. CONCLUSION: The phenotypic heterogeneity in this family, with an epilepsy syndrome determined by a single gene, was striking. This suggests that molecular genetic approaches to the common forms of idiopathic epilepsy, involving patients with clinically similar phenotypes from unrelated families, may be inappropriate.

Penetrance of the hereditary motor and sensory neuropathy Ia mutation: assessment by nerve conduction studies.

The clinical expression of hereditary motor and sensory neuropathy type I (HMSN I) is age-dependent. Autosomal dominant HMSN I is heterogeneous at a molecular level with genes localized on chromosomes 1, 17, and possibly other chromosomes. In order to define accurately the penetrance of a single HMSN I gene mutation, we performed nerve conduction studies in HMSN I families whose genetic defect was linked to chromosome 17 (HMSN Ia). All HMSN Ia subjects tested had slow nerve conduction velocities with a mean median velocity 20 +/- 6 m/sec, which did not change with age. The range of conduction velocities from affected individuals did not overlap those from their clinically normal relatives, indicating complete penetrance of the gene from early childhood. The results indicate that motor nerve conduction studies in children can add additional information for linkage studies and genetic counseling.

Efficient neurophysiologic selection of X-linked Charcot-Marie-Tooth families: ten novel mutations.

OBJECTIVE: To devise a neurophysiologic strategy to select X-linked Charcot-Marie-Tooth neuropathy syndrome (CMTX) families for connexin 32 mutation screening. BACKGROUND: Once the common chromosome 17 DNA duplication (CMT1A syndrome) has been excluded, clinical features are not sufficiently distinctive to select which of three genes (PMP22, Po, or connexin 32) should be screened for mutations. DESIGN: The yield of connexin 32 mutations was compared in possible CMTX families with clinical and genetic features of CMTX and probable CMTX families, defined by additional characteristic neurophysiologic features of CMTX. Of 232 CMT families with median motor nerve conduction velocities below 50 m/second (s) in affected men, 50 were found to have no CMT1A duplication and a pattern of inheritance compatible with CMTX (no man-to-man inheritance of CMT). These families were divided into 23 probable CMTX families (defined as having electrophysiologic indicators of CMTX), 23 possible CMTX families (with no neurophysiologic features of CMTX), and five unlikely CMTX families (with normal brainstem evoked auditory potentials [BAEPs]). RESULTS: The yield of mutations in the whole group was 25 mutations in 51 families (50%). Most probable CMTX families (21 of 23; 91%) had connexin 32 coding region mutations. Included in this group were 14 families with obligate female carriers; 11 of these had intermediate conduction velocities (>42 m/s) and nine (81%) had connexin 32 mutations. Only 3 of 23 (13%) possible CMTX families had connexin 32 mutations. One of five families with normal BAEPs in affected men had a connexin 32 mutation, and one had a Po Ala112Val mutation. Seventeen different mutations were found among 24 families, including 10 previously undescribed mutations (Leu9Trp, Ile28Thr, Ile30Thr, Ile127Met, Leu131Pro, Tyr154 stop, Pro158Ala, one base deletion of codon 158 causing stop at codon 195, Val192Phe, and Leu239Ile). CONCLUSIONS: The yield of connexin 32 mutations can be increased from approximately 6% of all CMT type I families to 91% of nonduplicated nondominant families with characteristic electrophysiologic changes of CMTX.

Lactate dehydrogenase isoenzyme in detecting carriers of Duchenne muscular dystrophy.

Thirty mothers of patients with Duchenne muscular dystrophy were studied with serum enzyme tests, including serum glutamic-oxaloacetic transminase, creatine kinase, and lactate dehydrogenase isoenzymes. In addition, females from the mothers' pedigrees were studied. Lactate dehydrogenase isoenzyme 5 determinations were as senitive an indicator of carrier status as creatine kinase and also identified several mothers who had normal dehydrogenase isoenzyme 5 determinations, as well as extensive pedigree testing, identified 28 to 30 mothers as probable heterozygotes. These data independently support the suggestion that cases of Duchenne muscular dystrophy as a result of spontaneous mutation are more uncommon than currently accepted.