LOPED study: looking for an early diagnosis in a late-onset Pompe disease high-risk population.

OBJECTIVE: A multicentre observational study was aimed to assess the prevalence of late-onset Pompe disease (LOPD) in a large high-risk population, using the dried blood spot (DBS) as a main screening tool. DESIGN/METHODS: 17 Italian neuromuscular centres were involved in the late-onset Pompe early diagnosis (LOPED) study. Inclusion criteria were: (1) age ≥5 years, (2) persistent hyperCKaemia and (3) muscle weakness at upper and/or lower limbs (limb-girdle muscle weakness, LGMW). Acid α-glucosidase (GAA) activity was measured separately on DBS by fluorometric as well as tandem mass spectrometry methods. A DBS retest was performed in patients resulted positive at first assay. For the final diagnosis, GAA deficiency was confirmed by a biochemical assay in skeletal muscle, whereas genotype was assessed by GAA molecular analysis. RESULTS: In a 14-month period, we studied 1051 cases: 30 positive samples (2.9%) were detected by first DBS screening, whereas, after retesting, 21 samples were still positive. Biochemical and molecular genetic studies finally confirmed LOPD diagnosis in 17 cases (1.6%). The median time from the onset of symptoms/signs to diagnosis was 5 years. Among those patients, 35% showed presymptomatic hyperCKaemia and 59% showed hyperCKaemia+LGMW, whereas 6% manifested with LGMW. CONCLUSIONS: LOPED study suggests that GAA activity should be accurately screened by DBS in all patients referring for isolated hyperCKaemia and/or LGMW. A timely diagnosis was performed in five patients with presymptomatic hyperCKaemia, but two had already manifested with relevant changes on muscle morphology and MRI. Consequently, enzyme replacement therapy was started in 14/17 patients, including the 2 patients still clinically presymptomatic but with a laboratory evidence of disease progression.

Italian recommendations for Lambert-Eaton myasthenic syndrome (LEMS) management.

Lambert-Eaton myasthenic syndrome (LEMS) is a pre-synaptic disorder of the neuromuscular and autonomic transmission mediated by antibodies to voltage-gated calcium channels at the motor nerve terminal. LEMS is a quite rare and probably under-diagnosed disease: the onset may be slow and clinical signs are typically fluctuating, thus adding to the delay in diagnosis. LEMS weakness typically involves lower and upper limbs and the proximal muscles are predominantly affected. A significant proportion of patients also have dysfunction of the autonomic nervous system that may include dry mouth, constipation, blurred vision, impaired sweating, and orthostatic hypotension. LEMS recognition is based on clinical, electrophysiological and immunological criteria. Nearly 50-60% of patients with LEMS have an underlying tumour that, in almost all cases, is a small-cell lung cancer; the onset of neurological symptoms generally precedes tumour detection. A careful screening for the early detection of the possible associated cancer is a crucial step for optimal disease management. The Italian Working Group on Myasthenic Syndromes developed diagnostic and therapeutic algorithms that could serve in routine clinical practice as tools for a patient-tailored approach.

Dissecting the prognostic signature of patients with astrocytoma isocitrate dehydrogenase-mutant grade 4: a large multicenter, retrospective study.

BACKGROUND: The World Health Organization (WHO) 2021 classification of central nervous system (CNS) tumors classified astrocytoma isocitrate dehydrogenase-mutant (A IDHm) with either microvascular proliferation and/or necrosis or homozygous deletion of CDKN2A/B as CNS grade 4 (CNS WHO G4), introducing a distinct entity and posing new challenges to physicians for appropriate management and prognostication. PATIENTS AND METHODS: We retrospectively collected information about patients diagnosed with A IDHm CNS WHO G4 at three reference neuro-oncological Italian centers and correlated them with survival. RESULTS: A total of 133 patients were included. Patients were young (median age 41 years) and most received post-operative treatment including chemo-radiation (n = 101) and/or temozolomide maintenance (n = 112). With a median follow-up of 51 months, the median overall survival (mOS) was 31.2 months, with a 5-year survival probability of 26%. In the univariate analysis, complete resection (mOS: 40.2 versus 26.3 months, P = 0.03), methyl-guaninemethyltransferase (MGMT) promoter methylation (mOS: 40.7 versus 18 months, P = 0.0136), and absence of telomerase reverse transcriptase (TERT) promoter mutation (mOS: 40.7 versus 18 months, P = 0.0003) correlated with better prognosis. In the multivariate models, lack of TERT promoter mutation [hazard ratio (HR) 0.23, 95% confidence interval (CI) 0.07-0.82, P = 0.024] and MGMT methylation (HR 0.40, 95% CI 0.20-0.81, P = 0.01) remained associated with improved survival. CONCLUSIONS: This is the largest experience in Western countries exploring the prognostic signature of patients with A IDHm CNS G4. Our results show that MGMT promoter methylation and TERT promoter mutation may impact clinical outcomes. This may support physicians in prognostication, clinical management, and design of future studies of this distinct diagnostic entity.

GCG genetic expansions in Italian patients with oculopharyngeal muscular dystrophy.

OBJECTIVE: To screen Italian patients with oculopharyngeal muscular dystrophy (OPMD) for GCG repeat expansions in the Poly(A) binding-protein 2 (PABP2) gene. BACKGROUND: Oculopharyngeal muscular dystrophy is an adult-onset autosomal dominant muscle disease linked to 14q11 pathologically characterized by unique 8.5 nm intranuclear filaments in skeletal muscle fibers. Short expansions of a (GCG)6 repeat located in exon 1 of the newly isolated PABP2 gene have been demonstrated in a large number of OPMD families. METHODS: We studied 18 patients diagnosed with OPMD. A muscle biopsy was performed in 16 patients. Screening for the pathologic expansion was performed on a PCR amplified DNA fragment encompassing the GCG repeat. RESULTS: Heterozygous (GCG)-repeat expansions were detected in 13 patients in association with (GCG)6 normal allele or (GCG)7 polymorphic allele. All the patients whose muscle biopsy showed typical 8.5 nm intranuclear filaments had a mutated PABP2 allele. Five patients with no intranuclear filaments were homozygous for the normal (GCG)6 allele. The pathologic expansion appeared to be stable with no variation among family members and between different tissues as blood and skeletal muscle in the same individual. CONCLUSIONS: These data 1) further confirm PABP2 gene analysis as a valuable tool in OPMD diagnosis; 2) indicate that PABP2 gene mutations are always present among Italian patients with morphologically proven OPMD, suggesting genetic homogeneity of the disease; and 3) strengthen the putative role of mutated PABP2 protein in filamentous inclusions accumulation.

Hepatitis C virus infection and myositis: a virus localization study.

We report a case of myositis associated with chronic hepatitis C virus infection. Muscle biopsy and immunohistochemistry showed perifascicular atrophy, few necrotic and regenerating fibres, scarce perivascular infiltrates, deposits of immunoglobulin G, C3, fibrinogen and MAC in muscle vessel walls, and non-uniform expression of major histocompatibility complex-I antigens among muscle fibres. Hepatitis C virus NS3 antigen and hepatitis C virus RNA were detected in infiltrating cells but not within muscle fibres or endothelial cells. Our findings suggest that humoral-mediated immune mechanisms, not directly related to hepatitis C virus infection of muscle structures, may sustain the local inflammatory reaction in this patient.

Macrophagic myofasciitis: an infantile Italian case.

Macrophagic myofasciitis is a recently identified inflammatory myopathy mostly described in adult French patients complaining of arthro-myalgias and fatigue. It is probably due to intramuscular injection of aluminium-containing vaccines and is characterized by a typical muscular infiltrate of large macrophages with aluminium inclusions. We report a 1-year-old Italian child presenting irritability, delayed motor development, hyperCKemia (up to 10 times the normal value), and typical features of macrophagic myofasciitis on muscle biopsy. The child recovered fully after steroid therapy. Macrophagic myofasciitis is a new treatable cause of motor retardation and hyperCKemia in children, and is probably more common than reported. Diagnosis requires a high index of suspicion and can be missed if biopsy is performed outside the vaccination site.

Facioscapulohumeral muscular dystrophy presenting isolated monomelic lower limb atrophy. Report of two patients with and without 4q35 rearrangement.

Facioscapulohumeral muscular dystrophy has a distinctive regional distribution but variable clinical expression and may be markedly asymmetrical. We report two patients presenting weakness and wasting confined to a single lower limb. Creatine kinase was slightly increased, electromyogram and muscle biopsy were myopathic. Muscle computed tomography showed normal shoulder, mid-arm, pelvic and mid-thigh scans but involvement of calf muscles. In both cases, weakness of facial and periscapular muscles was found in other family members unaware of the disease. Molecular analysis showed 4q35 deletion in one family. These cases broaden the presentation of facioscapulohumeral muscular dystrophy to include isolated monomelic atrophy of lower limb with calf muscle involvement.

Anti-GD1a antibodies from an acute motor axonal neuropathy patient selectively bind to motor nerve fiber nodes of Ranvier.

Acute motor axonal neuropathy (AMAN) is associated with high titer anti-GD1a antibodies. We have found that very high titer IgG anti-GD1a antibodies (Ab) from one AMAN patient selectively bind to motor, but not sensory, nerve nodes of Ranvier. Binding is abolished by preadsorption with GD1a. Sera negative for Ab do not immunostain motor and sensory nerve roots. We have also found that botulinum toxin A (BTA), which binds to GD1a, stains both motor and sensory nerve nodes of Ranvier. Our results strongly support the pathogenetic role of anti-GD1a antibodies in AMAN. Why BTA also binds to sensory fibers still remains to be elucidated, although the different size of BTA and its specificity to other gangliosides present in sensory axons might represent important factors.

Effect of rhTNF-alpha injection into rat sciatic nerve.

To assess whether TNF-alpha causes inflammatory demyelination or axonal degeneration, we injected into rat sciatic nerve saline, 100 U and 1000 U of rhTNF-alpha and studied the electrophysiological and pathological effects. At day 1 electrophysiology showed a slight reduction of proximal compound muscle action potential amplitude and pathology showed edema, inflammatory infiltration of vessel walls and endoneurium only in nerves injected with 1000 U of rhTNF-alpha. At day 5, there was no demyelination and a percentage of degenerated fibers similar in the three groups. To study the blood-nerve barrier, fluorescein isothiocyanate-labelled albumin was given intravenously after intraneural injection. The nerves injected with 1000 U rhTNF-alpha showed a leakage of the tracer in the endoneurium. TNF-alpha does not appear, at the doses used, to have myelinotoxic or axonopathic properties. The electrophysiological effect at day 1 may be due to mechanical compression of nerve fibers as a result of the blood-nerve barrier damage with consequent endoneurial edema.

Minimal and asymptomatic chronic inflammatory demyelinating polyneuropathy.

OBJECTIVES: Show the chronic inflammatory demyelinating polyneuropathy (CIDP) is not only clinically heterogeneous but extremely variable in severity. METHODS: Three patients were referred for mild distal paresthesiae lasting more than 6 months and one for inguinal and thigh pain later ascribed to coxarthrosis. Strength was normal in all patients and tactile sensation reduced distally only in one. Tendon jerks were absent, except the knee jerks in one patient, reduced in lower limbs in two and normal in one. RESULTS: Electrophysiology showed a demyelinating neuropathy without motor conduction block. CSF protein content was increased in all patients. Nerve biopsies showed de-remyelination with varying degrees of axonal loss. Genetic studies excluded a demyelinating neuropathy associated with duplication or deletion of the 17p.11.2 segment. CONCLUSIONS: CIDP patients with pure sensory clinical presentation have been described but are generally more severely impaired. However, because of the mildness of symptoms and the unequivocal electrophysiological involvement of motor fibers, we think that in these cases the term minimal CIDP is more appropriate than sensory CIDP. These cases represent the most benign end of the CIDP spectrum. In our series minimal or even asymptomatic CIDP encompasses 8% of cases.

Inter-nerves and intra-nerve conduction heterogeneity in CMTX with Arg(15)Gln mutation.

OBJECTIVE: In X-linked Charcot-Marie-Tooth disease (CMTX), electrophysiological and histopathological studies have suggested either a demyelinating or an axonal polyneuropathy. We report a CMTX family with a striking heterogeneity of nerve conductions between and within nerves. METHODS: Two men and one woman have been studied by conduction velocities, sural nerve biopsy with morphometry (one man) and DNA analysis. RESULTS: In both men motor conduction velocities were slowed in the demyelinating range, conduction velocity differences among nerves in the same subject varied from 13 to 24 m/s, and distal median compound muscle action potential (CMAP) amplitudes were 3-5 times reduced compared to ulnar CMAPs. Abnormal area reduction or excessive temporal dispersion of proximal CMAP was present in at least two nerves in all patients. Sural nerve biopsy showed reduction of large myelinated fibres, cluster formations, occasional onion bulbs. Teased fibres study revealed short internodes for fibre diameter, enlarged Ranvier nodes but no evidence of segmental demyelination and remyelination. DNA analysis showed an Arg(15)Gln mutation in connexin32 gene in all patients. CONCLUSIONS: In this family conduction slowing and segmental conduction abnormalities, in absence of morphological evidence of de-remyelination, may be related to short internodes, widened Ranvier nodes and the specific effect of the mutation. The occurrence in some CMTX patients of a non uniform involvement between and within nerves, as in acquired demyelinating neuropathies, should be kept in mind to avoid misdiagnoses.

Chronic inflammatory demyelinating polyneuropathy in diabetics: motor conductions are important in the differential diagnosis with diabetic polyneuropathy.

OBJECTIVE: It is important to recognize CIDP occurring in diabetics because, unlike diabetic polyneuropathy, it is treatable. The aim of this study was to find out whether there are clues which help to differentiate CIDP in diabetics from diabetic polyneuropathy. METHODS: We compared the electrophysiological and pathological findings of 7 diabetics, who developed a predominantly motor polyneuropathy with the features of CIDP, with a group of diabetics referred for symptomatic polyneuropathy. RESULTS: Of the 7 diabetics we believe developed CIDP, 6 met at least 3 and one patient two of the 4 electrophysiological criteria of demyelination. Of the 100 patients referred for diabetic polyneuropathy, only 4 fulfilled two criteria and none 3. Nerve biopsy findings were not helpful in differential diagnosis, as segmental demyelination and remyelination, onion bulbs and inflammatory infiltrates, which are the histologic features of CIDP, were also present in diabetic polyneuropathy. CONCLUSIONS: CIDP can be diagnosed in a diabetic patient when motor symptoms are predominant, are more severe than expected in diabetic polyneuropathy and 3 of the 4 electrophysiological criteria for demyelination are fulfilled. When only two criteria are met, we believe that a trial with one of the established treatments for CIDP may be helpful in confirming the diagnosis.

Benign monomelic amyotrophies of upper and lower limb are not associated to deletions of survival motor neuron gene.

Benign monomelic amyotrophies (BMAs) are rare conditions in which neurogenic atrophy is restricted either to the upper or lower limb. BMAs are usually sporadic, have insidious onset and slow progression followed by stabilization, are clinically confined for many years to a single limb and lack of sensory, bulbar, and pyramidal signs. Although the aetiology and pathogenesis of BMAs are unknown they are considered variants of spinal muscular atrophy with focal emphasis and a benign course. We studied 7 patients with BMAs to investigate whether they present alterations of the survival motor neuron gene (SMN) which has been found deleted or disrupted in proximal spinal muscular atrophy. All 7 patients showed the presence of both exon 7 and 8 of SMN gene. These findings indicate that deletions at the SMN locus are not present in BMA of upper and lower limb and suggest that these disorders are not only clinically but also genetically separate entities from proximal spinal muscular atrophies.

Benign monomelic amyotrophy of lower limb: a rare entity with a characteristic muscular CT.

Six patients presented with amyotrophy confined to a single lower limb and characterized by insidious onset, slow progression and later stabilization. Wasting was out of proportion with disability and there were no sensory, pyramidal tract or bulbar signs. All cases were sporadic, and there was no history of poliomyelitis. CK, anti-ganglioside antibodies, motor and sensory conductions were normal. Quantitative EMG and muscle biopsy revealed neurogenic features also in clinically unaffected limbs. Muscular CT showed selective or predominant, asymmetrical involvement of posterior leg muscles and caput longus of biceps femoris. Monomelic amyotrophy of lower limb is a clinically localized variant of spinal muscular atrophy with a particularly benign course. Although in the early stage there are no clinical or laboratory findings which allow differential diagnosis with other motor neuron diseases, the history of an amyotrophy clinically localized for more than 3 years to a lower single limb and the characteristic muscular CT pattern suggest the diagnosis since the first observation and indicate a favorable prognosis.

Abnormal brain and muscle energy metabolism shown by 31P-MRS in familial hemiplegic migraine.

Familial hemiplegic migraine (FHM) is a rare autosomal dominant disorder of unknown pathogenesis characterized by migraine and transitory hemiplegic attacks. We describe a kindred fulfilling the diagnostic criteria for FHM in which: (1) brain phosphorus magnetic resonance spectroscopy (31P-MRS) showed a reduced phosphocreatine content accompanied by high [ADP], high percentage of V/Vmax of ATP biosynthesis and decreased phosphorylation potential; (2) muscle 31P-MRS showed a reduced rate of phosphocreatine recovery after exercise; (3) blood lactate was increased after effort; (4) muscle biopsy showed, in one patient, rare ragged red fibers succinate-dehydrogenase positive and cytochrome c oxidase negative; (5) genetic analysis of muscle mitochondrial DNA did not show any of the two point mutations in the tRNA(Leu(UUR)) associated with the MELAS syndrome (Mitochondrial myopathy, Encephalopathy with Lactic Acidosis and Stroke-like episodes). The defective energy metabolism of brain and muscle found in this pedigree suggests a multisystemic disorder of mitochondrial function in this FHM pedigree.

A family with autosomal dominant distal arthrogryposis multiplex congenita and brown syndrome.

Arthrogryposis multiplex congenita is a heterogeneous condition found in a number of different disorders and characterized by congenital joint contractures. We describe typical signs of congenital Brown syndrome (inability to elevate the affected eye actively or passively in full adduction) in three relatives with distal arthrogryposis multiplex congenita. We found a thickening of the superior oblique muscles in these patients with pain and increased intraocular pressure in upgaze. The pathogenesis of clinical and morphological findings is discussed. The association of Brown syndrome with distal arthrogryposis multiplex congenita has not been previously reported and provides us with an important point of reference in the understanding of both syndromes.

Sympathetic skin response in hemispheric lesions.

We recorded the sympathetic skin response (SSR) from electrical nerve stimulation in 16 patients with cerebrovascular accident (CVA). Location and nature of the lesion were documented by computerized tomography (CT). Median (pre-rolandic and parietal) somatosensory evoked potentials (SEP) were also recorded. SSR was absent bilaterally in eight hemiplegics after stimulation of the plegic side and present bilaterally after stimulation of the normal side in the first weeks after CVA. Parietal and pre-rolandic SEPs were absent in the affected hemispheres. SSR was present bilaterally after stimulation of each side in the remaining CVA cases with reduced amplitude SEPs. Absence of the electrically evoked SSR in hemispheric lesions may be due to involvement of central afferent pathways or temporary suppression of suprasegmental excitatory influences.

Orthodromic median and ulnar fourth digit sensory conductions in mild carpal tunnel syndrome.

Because the fourth digit (D4) has a dual innervation, median and ulnar D4 sensory conduction velocity (SCV) comparison may be useful in diagnosing the carpal tunnel syndrome (CTS). We studied 50 control hands and 41 hands with recent onset symptoms and signs of CTS but normal median distal motor latency and normal SCV from the second digit (D2). In CTS, D4 SCV was significantly slower than D2 SCV and D4 median and ulnar sensory conduction difference was abnormal in 38 hands (92%). In 36 CTS hands (87%), but in no control hand, a double peak potential could be recorded over the median after D4 stimulation providing an immediate visual confirmation of the diagnosis of CTS. Comparing median and ulnar D4 SCV is a very sensitive method to detect early or mild CTS and should be used whenever conventional electrodiagnostic studies are normal or borderline.