Antonietta Topa

Central cholinergic dysfunction in the adult form of Niemann Pick disease type C: a further link with Alzheimer’s disease?

Adult patients with Niemann-Pick disease type C (NPC) usually develop cognitive impairment progressing to dementia, whose pathophysiology remains still unclear. Noteworthy parallels exist in cognitive impairment and cellular pathology of NPC and Alzheimer’s disease (AD). In particular, alterations of cholinergic system, which represent one of the pathological hallmarks and contribute to cognitive deterioration in AD, have recently been demonstrated in a human brain autopsy and in an experimental model of NPC. This finding raised the issue that central cholinergic circuits dysfunction may contribute to pathophysiology of cognitive impairment in NPC as well, and prompted us to evaluate the cholinergic functional involvement in NPC patients by applying a neurophysiologic technique, named short-latency afferent inhibition (SAI). We describe clinical, biochemical, molecular and neuropsychological features, and SAI findings in three patients affected by NPC. Diagnosis of NPC was assessed by molecular analysis of the NPC1 gene in all patients. In two of them, biochemical analysis of intracellular accumulation of unesterified cholesterol was also performed. The main clinical features were cerebellar ataxia, vertical supranuclear gaze palsy and a variable degree of cognitive impairment ranging from only memory impairment to severe dementia. Electrophysiological evaluation revealed a reduced SAI in all three patients. Our SAI findings provide evidence of cholinergic dysfunction in patients with the adult form of NPC, supporting that cholinergic alterations may play a role in cognitive impairment in NPC, and strengthening the similarities between NPC and AD.

Autonomic nervous system involvement in a new CMT2B family

We describe the first Italian family affected by CMT2B carrying a Val162Met substitution in the RAB7 gene. The clinical and electrophysiological features of our family are similar to those of previously reported families with RAB7 mutations, also for the higher occurrence of ulcers in males. However, in this family we evaluated the autonomic nervous system, never investigated in CMT2B, by means of skin biopsy and sudomotor and cardiovascular tests. Our findings provide both pathological and functional evidence of autonomic nervous system involvement in CMT2B and expand the phenotypic characterization of CMT2B disease.

Subclinical neurological involvement does not develop if Wilson's disease is treated early

BACKGROUND & AIMS Wilsons disease (WD) is a genetic disorder of copper metabolism causing dysfunctions of various organs, mostly the liver and brain. If untreated, WD is fatal, but early treatment results in a good prognosis, although the long-term neurological outcome has not yet been clarified. To address this issue, we evaluated the neurological status of early-treated WD patients without overt nervous system impairment using neurophysiological, neuropsychological and neuroimaging procedures at least 10 years after treatment onset. METHODS Thirty-eight WD patients (18 females, aged 24.47 ± 7.50 years), who received an early diagnosis (in presymptomatic or mild/moderate liver disease stages without neurological involvement) and prompt treatment, were clinically evaluated with the Global Assessment Scale. Presentation was hepatic in 36 subjects (95%), while 2 patients (5%) were presymptomatic. A neurophysiological study was performed to explore the central motor conduction time of the upper and lower limbs, and motor cortex excitability using single pulses and paired-pulse transcranial magnetic stimulation. Neuroimages were obtained with brain magnetic resonance scans. Cognitive abilities, and psychiatric and behavioral disturbances were evaluated with neuropsychological tests. RESULTS Patients were undergoing treatment with penicillamine (7 patients) or zinc salts (31 patients) with good adherence. They did not present any neurological signs at clinical evaluation or at specific scale of impairment, the mean Global Assessment Scale score was 0.3 ± 0.7. Magnetic resonance imaging, transcranial magnetic stimulation studies and neuropsychological/neuropsychiatric assessment ruled out subclinical involvement. CONCLUSIONS This study suggests that early diagnosis and treatment of WD may prevent the onset of neurologic damage, even at subclinical level.

Electrophysiological characterization of adult-onset Niemann-Pick type C disease

In infantile and juvenile Niemann-Pick type C (NPC) disease electrophysiological studies have shown central (CNS) and peripheral (PNS) nervous system abnormalities. However, an extensive electrophysiological evaluation of CNS and PNS in adult form of NPC is still lacking. The aim of the study is to assess in adult-onset NPC disease the involvement of CNS and PNS by a multimodal electrophysiological approach. Three patients affected by adult form of NPC disease underwent electrophysiological evaluation including nerve conduction study (NCS), magnetic motor (MEPs), visual (VEPs), somatosensory (SSEPs) and brainstem auditory (BAEPs) evoked potentials. NCS, MEPs, VEPs and upper limb SSEPs were normal. Lower limb SSEPs were abnormal in all patients and abnormalities were consistent with a length-dependent process affecting the central somatosensory pathway. BAEPs were abnormal in all patients with both peripheral and central impairment of auditory pathway. Our electrophysiological findings suggest that auditory and lower limb somatosensory pathways are constantly affected in adult-onset form of NPC disease. The involvement of PNS, pyramidal, visual and upper limb somatosensory pathways might occur later during the course of disease.

A novel autosomal dominant GDAP1 mutation in an Italian CMT2 family

We report the clinical, electrophysiological, and skin biopsy findings of an Italian Charcot‐Marie‐Tooth disease type 2 (CMT2) family with a novel heterozygous GDAP1 mutation. We observed a marked intra‐familial phenotypic variability, in age at onset and disease severity which ranged from a typical CMT phenotype to an asymptomatic status. Electrophysiological study, consistent with an axonal sensory‐motor neuropathy, confirmed a different degree of severity and disclosed minimal electrophysiological abnormalities also in the asymptomatic subjects. Skin biopsy findings showed a variable loss of large and small somatic nerve fibers. Molecular analysis identified a novel heterozygous missense mutation (Arg120Gly) in the GDAP1 gene which co‐segregated with the disease within the pedigree. In conclusion, our findings confirm that the GDAP1 autosomal dominant mutations underlie a pronounced phenotypic variability, mimicking the effects of reduced penetrance. Notably, electrophysiological study in this family allowed to reveal hidden positive family history and assess a dominant inheritance pattern, revealing subclinical neuropathy in asymptomatic mutation carriers.

Non-motor symptoms and cardiac innervation in SYNJ1-related parkinsonism

INTRODUCTION PARK20 is a rare autosomal recessive parkinsonism related to the SYNJ1 gene and characterized by early-onset of disease and atypical signs such as supranuclear vertical gaze palsy, dementia, dystonia, and generalized tonic-clonic seizures. OBJECTIVE Non-motor features and cardiac sympathetic innervation were assessed in two siblings affected by parkinsonism who harboured the homozygous Arg258Gln mutation in the SYNJ1 gene. METHODS The Non-Motor Symptoms, the SCOPA-AUT, the Mayo Sleep Questionnaires and polysomnography were used to investigate non-motor signs (NMS), autonomic dysfunction and REM Behavioural Disorder (RBD). Cognitive functions were examined by an extensive battery of neuropsychological tests. In addition, motor and sensory nerve conduction studies and evoked laser potentials were performed. Cardiac sympathetic innervation was assessed in the two patients by (123)I-metaiodobenzylguanidine (MIBG) scintigraphy, computing early and late heart-to-mediastinum (H/M) ratios and myocardial washout rates (WR). RESULTS Among the non-motor symptoms and autonomic signs, case 1 had cold intolerance, drooling and dysphagia, while case 2 had pain and urinary dysfunction. Both cases showed mood and behavioural disorders. RBD were not found, whereas the neuropsychological assessment revealed a progressive cognitive impairment. Neurophysiological studies revealed no abnormalities. Indexes of cardiac sympathetic innervation in the two patients did not differ from those of control subjects. CONCLUSIONS Our findings expand the phenotypic profile of SYNJ1-related parkinsonism. Preserved cardiac sympathetic function and absence of RBD suggest that PARK20 should be explained by a pathogenic mechanism different from Lewy Body pathology, or that the latter is not as widespread as idiopathic Parkinsons disease.

Motor performance deterioration accelerates after 50 years of age in Charcot‐Marie‐Tooth type 1a patients

The aim of our study was to describe, by a case‐control and cross‐sectional design, the correlation between clinical impairment and age in Charcot‐Marie‐Tooth type 1A (CMT1A) patients.

Chronic inflammatory demyelinating polyneuropathy mimicking an acute painful diabetic neuropathy.

Acute diabetic painful neuropathy associated with weight loss, also known as ‘‘diabetic neuropathic cachexia’’, presents with severe burning pain, particularly in the feet and the onset is associated with weight loss. Clinical features are the presence of allodynia and hyperalgesia, as well as depression and erectile dysfunction. There are commonly no motor signs and nerve conduction studies are also usually normal or mildly abnormal [1]. Moreover, relapses are not typically observed [2]. Herein, we report a patient with chronic inflammatory demyelinating polyneuropathy (CIDP) presenting with a clinical picture resembling that of acute diabetic painful neuropathy. The patient, a 56-year-old man affected by type 2 diabetes mellitus and on hypoglycemic drug, referred to our Institute with a 3-month history of acute-onset painful neuropathy at lower limbs associated with unintentional weight loss (10 kg). He complained of intense burning and stabbing pain worsened by clothing and bedding, and associated with sensations of needles involving the thighs. Additionally, he complained of distal paresthesia, fatigue and autonomic disturbances as impotence and paroxysmal episodes of profuse sweating. Pharmacological management of pain provided only minimal relief. The patient appeared pale and to be chronically ill (BMI = 17.3, nv = 18.5–24.9). His mood was also depressed. Neurological examination showed the absence of ankle reflexes, decreased sensitivity to light touch and pinprick in the feet, and allodynia and hyperalgesia at the thighs. Muscular strength and vibration sense were preserved. Electrodiagnostic testing revealed a primary demyelinating sensory-motor polyneuropathy and a diagnosis of CIDP was assessed (Table 1) [3]. Cerebrospinal fluid examination showed an increased protein level (1.1 g/L, normal range 0.15–0.45 g/L). An extensive laboratory workup to rule out other acquired causes of neuropathy was negative. Serum glucose and glycosylated hemoglobin levels were also within the normal range. The patient received intravenous immunoglobulin (IVIG) treatment (400 mg/kg/day for 5 days) and in the following weeks, fatigue and sensory complaints significantly improved and autonomic dysfunctions resolved. At neurological examination allodynia and hyperalgesia were not observed whereas nerve conduction study was unchanged. The improvement lasted 3 months after which the patient needed IVIG treatment again for pain reappearance. At 6-month follow-up after the second IVIG treatment the patient still complained of fatigue and dysesthesias at lower limbs. In this patient, the clinical picture at onset resembled that of acute diabetic painful neuropathy but electrophysiological study showed demyelinating features consistent with CIDP. Increased protein level in cerebrospinal fluid (CSF) corroborated this diagnosis as well. CIDP encompasses typical clinical picture and several different atypical variants, including sensory-predominant CIDP [3]. The sensory-predominant form of CIDP is characterized clinically by sensory symptoms and signs including pain that can also represent the major presenting symptom of CIDP. Despite the lack of weakness, the nerve conduction studies demonstrated significant motor A. Topa R. Dubbioso R. Iodice L. Santoro F. Manganelli (&) Department of Neurosciences, Reproductive Sciences and Odontostomatology, University Federico II of Naples, Via Sergio Pansini, 5, 80131 Naples, Italy e-mail: fiore.manganelli@unina.it

A Case of Late-Onset Pompe Disease Occurring with a Muscle Weakness Pattern Similar to that of Facioscapulohumeral Muscular Dystrophy

Pompe or glycogen storage disease type II is an autosomal recessive disorder, caused by an accumulation of glycogen in the lysosome. The clinical spectrum ranges from the classic form with early onset and severe phenotype to the non-classic form with later onset and different phenotype. In fact, the clinical presentation of Pompe disease can resemble that of many musculoskeletal disorders. According to the clinical variability of the disease, we report a 48-yearold man with the adult form of acid maltase defi ciency showing many clinical similarities to facioscapulohumeral muscular dystrophy (FSHD).