Chiara Fiorillo

Sudden re-opening of collapsed transverse sinuses and longstanding clinical remission after a single lumbar puncture in a case of idiopathic intracranial hypertension. Pathogenetic implications

The aetiopathogenetic role of sinus venous obstructions carried by most idiopathic intracranial hypertension (IIH) patients is controversial. We report the case of a young woman diagnosed with IIH with papilloedema and narrowing of transverse sinuses, in which lowering of intracranial pressure by a single 20 ml cerebrospinal fluid (CSF) resulted in a strong dimensional increase of the transverse sinuses. Changes were followed by clinical remission and normalisation of optical nerve calibre, maintained after a 2-month follow-up. Our findings indicate that, although secondary to CSF hypertension, venous sinuses compression may have an important role in hypertensive status maintenance. Pathogenetic implications of venous sinus compression by hypertensive CSF in IIH are discussed.

Novel dynein DYNC1H1 neck and motor domain mutations link distal spinal muscular atrophy and abnormal cortical development

DYNC1H1 encodes the heavy chain of cytoplasmic dynein 1, a motor protein complex implicated in retrograde axonal transport, neuronal migration, and other intracellular motility functions. Mutations in DYNC1H1 have been described in autosomal‐dominant Charcot–Marie–Tooth type 2 and in families with distal spinal muscular atrophy (SMA) predominantly affecting the legs (SMA‐LED). Recently, defects of cytoplasmic dynein 1 were also associated with a form of mental retardation and neuronal migration disorders. Here, we describe two unrelated patients presenting a combined phenotype of congenital motor neuron disease associated with focal areas of cortical malformation. In each patient, we identified a novel de novo mutation in DYNC1H1: c.3581A>G (p.Gln1194Arg) in one case and c.9142G>A (p.Glu3048Lys) in the other. The mutations lie in different domains of the dynein heavy chain, and are deleterious to protein function as indicated by assays for Golgi recovery after nocodazole washout in patient fibroblasts. Our results expand the set of pathological mutations in DYNC1H1, reinforce the role of cytoplasmic dynein in disorders of neuronal migration, and provide evidence for a syndrome including spinal nerve degeneration and brain developmental problems.

Centronuclear myopathy related to dynamin 2 mutations: Clinical, morphological, muscle imaging and genetic features of an Italian cohort

Mutations in dynamin 2 (DNM2) gene cause autosomal dominant centronuclear myopathy and occur in around 50% of patients with centronuclear myopathy. We report clinical, morphological, muscle imaging and genetic data of 10 unrelated Italian patients with centronuclear myopathy related to DNM2 mutations. Our results confirm the clinical heterogeneity of this disease, underlining some peculiar clinical features, such as severe pulmonary impairment and jaw contracture that should be considered in the clinical follow-up of these patients. Muscle MRI showed a distinct pattern of involvement, with predominant involvement of soleus and tibialis anterior in the lower leg muscles, followed by hamstring muscles and adductor magnus at thigh level and gluteus maximus. The detection of three novel DNM2 mutations and the first case of somatic mosaicism further expand the genetic spectrum of the disease.

Facioscapulohumeral muscular dystrophy: new insights from compound heterozygotes and implication for prenatal genetic counselling

Background Facioscapulohumeral muscular dystrophy (FSHD) is considered an autosomal dominant disease with a prevalence of 1 in 20 000. Almost all patients with FSHD carry deletions of integral copies of tandem 3.3 kb repeats (D4Z4) located on chromosome 4q35. However, FSHD families have been reported in which individuals carrying a D4Z4-reduced allele remain asymptomatic. Recently, it has been proposed that the D4Z4-reduced allele is pathogenic only in association with the permissive haplotype, 4APAS. Methods and results Through the Italian National Registry for FSHD (INRF), genotype–phenotype correlations were extensively studied in 11 non-consanguineous families in which two D4Z4-reduced alleles segregate. Overall, 68 subjects carrying D4Z4-reduced alleles were examined, including 15 compound heterozygotes. It was found that in four families the only FSHD-affected subject was the compound heterozygote for the D4Z4-reduced allele, and 52.6% of subjects carrying a single D4Z4-reduced 4A161PAS haplotype were non-penetrant carriers; moreover, the population frequency of the 4A161PAS haplotype associated with a D4Z4-reduced allele was found to be as high as 1.2%. Conclusions This study reveals a high frequency of compound heterozygotes in the Italian population and the presence of D4Z4-reduced alleles with the 4A161PAS pathogenic haplotype in the majority of non-penetrant subjects in FSHD families with compound heterozygosity. These data suggest that carriers of FSHD-sized alleles with 4A161PAS haplotype are more common in the general population than expected on the basis of FSHD prevalence. These findings challenge the notion that FSHD is a fully penetrant autosomal dominant disorder uniquely associated with the 4A161PAS haplotype, with relevant repercussions for genetic counselling and prenatal diagnosis.

Genotype-phenotype correlations in a large series of patients with muscle type CPT II deficiency

Abstract Objectives: The adult or ‘muscular’ form of carnitine-palmitoyl-transferase II (CPT II) deficiency presents with recurrent rhabdomyolytic episodes and myoglobinuria, usually triggered by prolonged exercise. The aim of this study was to investigate a large series of patients in order to provide genotype-phenotype correlations. Methods: Our muscle tissue bank was surveyed for patients showing attacks of rhabdomyolysis with myoglobinuria. After exclusion of cases affected with toxic myoglobinuria, McArdles disease and Becker muscular dystrophy, over 100 patients were selected for isotope-exchange radioenzymatic assay of CPT enzyme activity in muscle, and 25 cases resulted to be defective. Acylcarnitine profile was performed in five patients using tandem mass spectrometry. Mutations in the CPT2 gene were identified using DNA sequencing. Results: Although the clinical features were rather homogeneous, some patients presented life-threatening events (acute renal failure) and muscle weakness, and low levels of residual CPT activity. The typical acylcarnitine profile found in mutant patients confirmed its value as a screening method for further diagnostic investigations. We found a high frequency of the common p.Ser113Leu mutation, the recurrence of the rare p.Arg631Cys mutation in a genetic isolate in Southern Italy, and identified four novel mutations. In some affected patients only one mutant allele was found, suggesting either incomplete mutation detection or the possibility they are symptomatic carriers. Discussion: Null mutations and homozygous mutations were frequently associated with a more severe phenotype and biochemical defect. The identification of symptomatic obligate heterozygous carriers might suggest that additional epigenetic or environmental factors may contribute to determine the phenotype.

Cranial neuralgias: from physiopathology to pharmacological treatment

Cranial neuralgias are paroxysmal painful disorders of the head characterised by some shared features such as unilaterality of symptoms, transience and recurrence of attacks, superficial and “shock-like” quality of pain and the presence of triggering factors. Although rare, these disorders must be promptly recognised as they harbour a relatively high risk for underlying compressive or inflammatory disease. Nevertheless, misdiagnosis is frequent. Trigeminal and glossopharyngeal neuralgias are sustained in most cases by a neurovascular conflict in the posterior fossa resulting in a hyperexcitability state of the trigeminal circuitry. If the aetiology of trigeminal neuralgia (TN) and other typical neuralgias must be brought back to the peripheral injury, their pathogenesis could involve central allodynic mechanisms, which, in patients with inter-critical pain, also engage the nociceptive neurons at the thalamic-cortical level. Currently available medical treatments for TN and other cranial neuralgias are reviewed.

Acetazolamide efficacy and tolerability in migraine with aura : A pilot study

The study was an open uncontrolled pilot trial to test the efficacy and the tolerability of acetazolamide in a group of 22 outpatients suffering from migraine with aura (MA) with at least one aura episode in the last 2 months.

A cluster headache family with possible autosomal recessive inheritance

Until the early 1990s, cluster headache (CH) was considered a sporadic disorder, with a prevalence of 69 per 100,000.1 The presence of CH in monozygotic twins2 and in first- and second-degree relatives3 suggested that genetic factors might be involved. Based on a mailed questionnaire, the prevalence of familial CH was 7%, and based on personal examination of alleged familial cases, it was 30%.3 A large epidemiologic study suggested autosomal dominant inheritance can be involved in some families.4 The current study describes a large kindred in which an autosomal recessive model could be involved. The pedigree (figure) includes four related families from the Naples area (southern Italy). The proband (IV-1), diagnosed in March 2000, referred other relatives possibly affected. All living members were interviewed by telephone, and all possibly affected members were evaluated by a neurologist experienced in CH. Clinical information about deceased individuals, obtained from their descendants, allowed us to exclude CH. Figure. Pedigree of a large kindred of four related families in which eight members …

The genetic basis of undiagnosed muscular dystrophies and myopathies Results from 504 patients

Objective: To apply next-generation sequencing (NGS) for the investigation of the genetic basis of undiagnosed muscular dystrophies and myopathies in a very large cohort of patients. Methods: We applied an NGS-based platform named MotorPlex to our diagnostic workflow to test muscle disease genes with a high sensitivity and specificity for small DNA variants. We analyzed 504 undiagnosed patients mostly referred as being affected by limb-girdle muscular dystrophy or congenital myopathy. Results: MotorPlex provided a complete molecular diagnosis in 218 cases (43.3%). A further 160 patients (31.7%) showed as yet unproven candidate variants. Pathogenic variants were found in 47 of 93 genes, and in more than 30% of cases, the phenotype was nonconventional, broadening the spectrum of disease presentation in at least 10 genes. Conclusions: Our large DNA study of patients with undiagnosed myopathy is an example of the ongoing revolution in molecular diagnostics, highlighting the advantages in using NGS as a first-tier approach for heterogeneous genetic conditions.

Is idiopathic intracranial hypertension without papilledema a risk factor for migraine progression

The association of chronic migraine (CM) with an idiopathic intracranial hypertension without papilledema (IIHWOP), although much more prevalent than expected in clinical series of CM sufferers, is not included among the risk factors for migraine progression. We discuss the available evidence supporting the existence of a pathogenetic link between CM and idiopathic intracranial hypertensive disorders and suggest a causative role for IIHWOP in migraine progression.