Treadmill training in patients affected by Charcot-Marie-Tooth neuropathy: results of a multicenter, prospective, randomized, single-blind, controlled study.

BACKGROUND AND PURPOSE: Muscle-strengthening, stretching or proprioceptive treatments may slow symptom progression in Charcot-Marie-Tooth (CMT) neuropathy. The aim of the study was to evaluate safety and efficacy of treadmill training in CMT1A. METHODS: We planned a multicenter, prospective, randomized, single-blind, controlled study. We recruited 53 outpatients affected by CMT1A and randomized them into two treatment groups: one underwent stretching and proprioceptive exercise, whereas the other was additionally treated with treadmill training (TreSPE). Primary outcome measures (OMs) were the walking evaluations and secondary OM was the balance assessment. All participants were assessed at baseline and after 3 and 6 months of treatment. RESULTS: Most patients showed an improvement in at least one OM after 3 months [42/47 (89.4%)] and 6 months [38/40 (95%)] of treatment. No adverse events were reported in either group. CONCLUSIONS: The most important finding was that both stretching and proprioceptive exercise and treadmill training had an objective benefit on patients affected by CMT disease, without causing overwork weakness. We had a low rate of drop out and did not find deterioration in motor performance. Our results also confirm that applying evidence-based medicine methods to rehabilitative research is the correct way to test the efficacy of a treatment.

Novel outcome measures for Charcot-Marie-Tooth disease: validation and reliability of the 6-min walk test and StepWatch(™) Activity Monitor and identification of the walking features related to higher quality of life.

BACKGROUND AND PURPOSE: Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy, but therapeutic options have been limited to symptom management. Past pharmacological trials have failed, possibly due to insensitive outcome measures (OMs). The aim of the current study was to evaluate the validity and reliability of the 6-min walk test (6MWT) and StepWatch(™) Activity Monitoring (SAM) with other previously validated OMs in CMT disease. METHODS: A prospective multicenter study was performed, consecutively enrolling 168 CMT patients (104 with CMT1A, 27 with CMT1B, 37 with X-linked CMT) from Italian centers specializing in CMT care. RESULTS: Statistical analysis showed that the 6MWT was highly related with all previously used OMs. Some, but not all, SAM parameters were related to commonly used OMs but may provide more information about quality of life. CONCLUSIONS: The current study demonstrated the validity and reliability of the 6MWT and SAM as OMs for CMT. Moreover, SAM provides data that correlate better with quality of life measures, making it useful in future rehabilitation trials.

Nerve conduction velocity in CMT1A: what else can we tell?

BACKGROUND AND PURPOSE: Charcot-Marie-Tooth disease (CMT) type 1A is characterized by uniformly reduced nerve conduction velocity (NCV) that is fully penetrant since the first years of life, remains fairly stable through the life and does not correlate with disability whereas compound muscular action potential (CMAP) amplitude does. The aim of the present study was to analyze the large amount of electrophysiological data collected in the ascorbic acid trial in Italy and the UK (CMT-TRIAAL/CMT-TRAUK) and to use these data to gain insights into the pathophysiology of NCV in CMT1A. METHODS: Baseline electrophysiological data from 271 patients were analysed. Electrophysiological recordings were taken from the motor ulnar, median and peroneal nerves and the sensory ulnar nerve. Distal motor latency (DML), motor (MNCV) and sensory (SNCV) nerve conduction velocity, and amplitudes of CMAPs and sensory action potentials were assessed. Electrophysiological findings were correlated with age of patients at examination and the Charcot-Marie-Tooth Examination Score (CMTES). RESULTS: NCV was markedly and uniformly reduced. CMAP amplitudes were overall reduced but more severely in lower limbs. DML decreased and MNCV and SNCV increased with age of the patients, whereas CMAP amplitudes worsened with age and also correlated with CMTES. CONCLUSIONS: This is the largest sample of electrophysiological data obtained so far from CMT1A patients. Axonal degeneration as assessed by means of CMAP amplitude reflected clinical impairment and was consistent with a slowly progressive length-dependent neuropathy. All patients typically had markedly slowed NCV that did, however, slightly increase with age of the patients. The improvement of NCV might depend on myelin thickness remodelling that occurs during the adult life of CMT1A patients.

Fusidic acid betamethasone lipid cream.

Bacterial infections of the skin and soft tissues are frequent disorders. They can be primitive infections (e.g. impetigo, folliculitis) or secondary infections complicating other diseases, particularly atopic dermatitis. The most common aetiologic agent is Staphylococcus aureus. Topical antibiotic therapy may be sufficient in many instances to control these infections. Fusidic acid is an antibiotic used topically on the skin which is very active against S. aureus, including methicillin-resistant strains, and other Gram-positive bacteria. Resistance rates to fusidic acid are stably low. A fusidic acid and betamethasone formulation in a lipid-enriched cream (lipid cream) has been recently developed in order to provide effective antibacterial and anti-inflammatory activities in conjunction with a powerful emollient and moisturising effect. This preparation may be especially useful in patients with atopic-infected eczema.

Responsiveness of clinical outcome measures in Charcot-Marie-Tooth disease.

BACKGROUND AND PURPOSE: Charcot-Marie-Tooth disease (CMT) is a very slowly progressive neuropathy which makes it difficult to detect disease progression over time and to assess intervention efficacy. Experience from completed clinical trials with ascorbic acid and natural history studies confirm difficulties in detecting such changes. Consequently, sensitive-to-change outcome measures (OMs) are urgently needed. METHODS: The relative responsiveness of clinical scales of the Italian-UK ascorbic acid trial (placebo arm) were assessed by using the standardized response mean (SRM), which is the ratio of the paired scores mean change over time to the standard deviation of the score change (0 is worst responsiveness). RESULTS: Little worsening of OM scores was found over 2 years. In detail, the primary OM of the trial, the CMT Neuropathy Score version 1 (CMTNSv1), showed low responsiveness (SRM 0.13). Some CMTNS items showed slightly greater responsiveness (CMT Examination Score 0.17; CMTNS Signs 0.19). Myometric assessments of handgrip and foot dorsiflexion strength were the most responsive (SRM -0.31 and -0.38, respectively). Amongst the other measures, the nine-hole peg test, which assesses upper limb functioning, showed the best sensitivity to change (SRM 0.28). CONCLUSIONS: Overall these OMs showed low or negligible responsiveness, confirming the need to improve current OMs and to develop novel ones for prognostic and interventional studies. However, handgrip and foot dorsiflexion myometry are worth retaining for future trials as they were the most responsive and are likely to be clinically relevant for patients.

Is overwork weakness relevant in Charcot-Marie-Tooth disease?

BACKGROUND: In overwork weakness (OW), muscles are increasingly weakened by exercise, work or daily activities. Although it is a well-established phenomenon in several neuromuscular disorders, it is debated whether it occurs in Charcot-Marie-Tooth disease (CMT). Dominant limb muscles undergo a heavier overload than non-dominant and therefore if OW occurs we would expect them to become weaker. Four previous studies, comparing dominant and non-dominant hand strength in CMT series employing manual testing or myometry, gave contradictory results. Moreover, none of them examined the behaviour of lower limb muscles. METHODS: We tested the OW hypothesis in 271 CMT1A adult patients by comparing bilateral intrinsic hand and leg muscle strength with manual testing as well as manual dexterity. RESULTS: We found no significant difference between sides for the strength of first dorsal interosseous, abductor pollicis brevis, anterior tibialis and triceps surae. Dominant side muscles did not become weaker than non-dominant with increasing age and disease severity (assessed with the CMT Neuropathy Score); in fact, the dominant triceps surae was slightly stronger than the non-dominant with increasing age and disease severity. DISCUSSION: Our data does not support the OW hypothesis and the consequent harmful effect of exercise in patients with CMT1A. Physical activity should be encouraged, and rehabilitation remains the most effective treatment for CMT patients.

An update on juvenile dermatomyositis.

Juvenile dermatomyositis (JDM) is a rare, severe, autoimmune disease characterized by a small-vessel vasculopathy that primarily affects skin and muscle, but also lung, joints, gut and heart. Nowadays prompt recognition of this entity and aggressive treatment, when needed, improves outcomes and has decreased mortality that, before corticosteroid became a mainstay in therapy, could reach 40%.

Psoriasis and seborrheic dermatitis in infancy and childhood.

Psoriasis is a common inflammatory dermatosis that may be seen in infants, children, and adolescents. The clinical presentation and course may be quite variable, and while patients with mild disease are often easily managed, those with recalcitrant or more severe disease often present a therapeutic dilemma given the number of therapies available and the relative lack of data on the efficacy and safety of use of these therapies in children. Diagnosis in children can be more difficult, but family history may be helpful. Moreover, sometimes clinical pattern of pediatric psoriasis is very different from its adult counterpart or it could manifests in association with atopic dermatitis, and for these reason it is possibly misdiagnosed and under recognized. We therefore focus on diagnostic patterns and effective treatments of this challenging disease.

A conserved sorting-associated protein is mutant in chorea-acanthocytosis.

Chorea-acanthocytosis (CHAC, MIM 200150) is an autosomal recessive neurodegenerative disorder characterized by the gradual onset of hyperkinetic movements and abnormal erythrocyte morphology (acanthocytosis). Neurological findings closely resemble those observed in Huntington disease. We identified a gene in the CHAC critical region and found 16 different mutations in individuals with chorea-acanthocytosis. CHAC encodes an evolutionarily conserved protein that is probably involved in protein sorting.

Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria.

The gene products involved in mammalian mitochondrial DNA (mtDNA) maintenance and organization remain largely unknown. We report here a novel mitochondrial protein, Twinkle, with structural similarity to phage T7 gene 4 primase/helicase and other hexameric ring helicases. Twinkle colocalizes with mtDNA in mitochondrial nucleoids. Screening of the gene encoding Twinkle in individuals with autosomal dominant progressive external ophthalmoplegia (adPEO), associated with multiple mtDNA deletions, identified 11 different coding-region mutations co-segregating with the disorder in 12 adPEO pedigrees of various ethnic origins. The mutations cluster in a region of the protein proposed to be involved in subunit interactions. The function of Twinkle is inferred to be critical for lifetime maintenance of human mtDNA integrity.

Systemic lupus erythematosus developing immediately after necrotizing fasciitis.

Necrotizing fasciitis (NF) is a medical-surgical emergency characterized by severe bacterial infection that affects the subcutaneous tissue and spreads to the underlying fascia; usually it is caused by penetrating trauma, sometimes by surgical therapy, very rarely by minor insults such as insect bites. Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease involving virtually all the key components of the immune system. Although cases of post-infection autoimmunity were already described, a literature search using Pub Med and Medline revealed that SLE was never reported to occur in patients affected, immediately before, with NF. We observed and herein report, however, a case of a woman showing an insect-bite-induced NF, which was immediately followed by the development of a SLE. In conclusion, this case of postinfection autoimmunity provides early evidence of a patient developing SLE immediately after NF, and suggests that caution in the follow-up of NF is necessary, because NF might favor the development of a severe autoimmunity.

Topical clindamycin 1% vs. linoleic acid-rich phosphatidylcholine and nicotinamide 4% in the treatment of acne: a multicentre-randomized trial.

It has been shown that topical linoleic acid rich-phosphatidylcholine seems to be effective in normalization of follicular hyperkeratinization, whereas nicotinamide has an interesting anti-inflammatory effect. However, little is known about their combined effect on acne. A multicentre, double-blind, 12-week randomized vehicle and parallel-active control study was conducted by clinical and biophysical non-invasive measurements to evaluate the efficacy, tolerability and safety of a 4% nicotinamide-phospholipidic (N-PHCL) emulsion vs. 1% topical clindamycin phosphate applied once daily. Four percentage N-PHCL cosmetic treatment resulted slightly superior to topical clindamycin with all the parameters studied for its better compliance and the global clinical improvement.

Seipin S90L mutation in an Italian family with CMT2/dHMN and pyramidal signs.

Heterozygous mutations in the Berardinelli-Seip congenital lipodystrophy (BSCL2) gene have been associated with different clinical phenotypes including Silver syndrome/spastic paraplegia 17, distal hereditary motor neuropathy type V, and Charcot-Marie-Tooth disease type 2 (CMT2) with predominant hand involvement. We studied an Italian family with a CMT2 phenotype with pyramidal signs that had subclinical sensory involvement on sural nerve biopsy. Direct sequencing analysis of the BSCL2 gene in the three affected siblings revealed an S90L mutation. This report confirms the variability of clinical phenotypes associated with a BSCL2 Ser90Leu mutation and describes the first Italian family with this mutation.

Sustained response to subcutaneous immunoglobulins in chronic ataxic neuropathy with anti-disialosyl IgM antibodies (CANDA): report of two cases and review of the literature.

INTRODUCTION: Chronic ataxic neuropathy with anti-disialosyl IgM antibodies (CANDA) is a rare disorder for which the pathological, neurophysiological, and therapeutic evidence remains anecdotal and controversial. METHODS: This report on CANDA focuses on the neurophysiological patterns and treatment responses shared by two cases. One patient underwent nerve ultrasound follow-up. A comprehensive review of the literature highlighted the diverse experiences with different treatment options. RESULTS: Response to different therapies was similar in both patients: intravenous immunoglobulins achieved a favorable response albeit with significant wearing-off fluctuations; treatment with subcutaneous immunoglobulins (SCIg) was an effective alternative leading to a clinical response for at least 2 years. Rituximab, which was trialed in both patients, was not continued long enough to determine its efficacy in modifying the disease course and/or modulating responsiveness to immunoglobulins. Steroids caused clinical worsening in both patients. CONCLUSIONS: Immunoglobulin therapy appeared as the most effective in the treatment of these two patients. SCIg provided an effective treatment option for the long-term management of CANDA.

Recommendations for pre-symptomatic genetic testing for hereditary transthyretin amyloidosis in the era of effective therapy: a multicenter Italian consensus.

Hereditary transthyretin amyloidosis (ATTRv, v for variant) is a late-onset, autosomal dominant disease caused by progressive extracellular deposition of transthyretin amyloid fibrils, leading to organ damage and death. For other late-onset fatal diseases, as Huntington's disease, protocols for pre-symptomatic genetic testing (PST) are available since decades. For ATTRv, limited experience has been reported to date, mostly gathered before the availability of approved therapies. We aimed at developing recommendations for a safe and feasible PST protocol in ATTRv in the era of emerging treatments, taking also into account Italian patients' characteristics and healthcare system rules. After an initial survey on ongoing approaches to PST for ATTRv in Italy, two roundtable meetings were attended by 24 experts from 16 Italian centers involved in the diagnosis and care of this disease. Minimal requirements for PST offer and potential critical issues were highlighted. By November 2019, 457 families affected by ATTRv with 209 molecularly confirmed pre-symptomatic carriers were counted. The median age at PST was 41.3 years of age, regardless of the specific mutation. Half of the Italian centers had a multidisciplinary team, including a neurologist, an internist, a cardiologist, a medical geneticist and a psychologist, although in most cases not all the specialists were available in the same center. A variable number of visits was performed at each site. Experts agreed that PST should be offered only in the context of genetic counselling to at risk individuals aged 18 or older. Advertised commercial options for DNA testing should be avoided. The protocol should consist of several steps, including a preliminary clinical examination, a pre-test information session, an interval time, the genetic test and a post-test session with the disclosure of the test results, in the context of an experienced multidisciplinary team. Recommendations for best timing were also defined. Protocols for PST in the context of ATTRv can be refined to offer at risk individuals the best chance for early diagnosis and timely treatment start, while respecting autonomous decisions and promoting safe psychological adjustment to the genetic result.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy and right-to-left shunt: lack of evidence for an association in a prevalence study.

BACKGROUND/AIMS: Up to more than 50% of cryptogenetic stroke patients and patients with migraine with aura (MA) are found to have a right-to-left shunt (RLS), which is usually due to a patent foramen ovale. Moreover, both MA and stroke are cardinal features of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Notch3 mutations have been suggested to induce an abnormally high incidence of atrial septal defects in a family harbouring an Arg141Cys pathogenetic mutation. We sought to determine the prevalence of RLS in CADASIL patients with different Notch3 mutations, both with and without migraine as a clinical feature. METHODS: Subjects with a molecular diagnosis of CADASIL were tested for the presence of an RLS by means of contrast-enhanced transcranial Doppler (TCD). The diagnosis of migraine was made according to the 2004 International Headache Classification. RESULTS: Sixteen CADASIL patients were tested; 6 had MA. Four patients displayed an RLS on contrast-enhanced TCD examination. Three of these patients had MA. Both patients with Arg141Cys displayed a large RLS. CONCLUSION: We conclude that RLS is not necessarily linked to CADASIL as a comorbidity factor. Nevertheless, there could be a relation between RLS and specific Notch3 mutations, such as Arg141Cys.

Extragenital lichen sclerosus and atrophicus treated with topical steroids and retinoids in a child with vitiligo.

Lichen sclerosus and atrophicus (LSA) most commonly affects the anogenital region. Extragenital involvement is rare, and women are reported to be affected 6 to 10 times more often than men. The aetiology of LSA is unclear, but genetic, physiological and environmental factors are thought to be involved. Several lines of evidence support the hypothesis of an autoimmune basis for LSA; an increased incidence of tissue-specific antibodies and an association with autoimmune disorders such as vitiligo, alopecia areata, thyroid disease and pernicious anaemia have been reported. We describe a paediatric patient with extragenital LSA associated with vitiligo who was successfully treated with topical steroids and retinoids.