Fernando George Monteiro Naylor

New findings in facial-onset sensory and motor neuronopathy (FOSMN) syndrome

Facial-onset sensory and motor neuronopathy (FOSMN) syndrome represents a rare, slowly progressive, lower motor neuron disease with sensory compromise, involving mainly the face, bulbar region and upper limbs. However, non-motor symptoms and neurogenetic studies have rarely been evaluated in large case series. In the present study, 10 unrelated Brazilian patients with FOSMN syndrome underwent extensive clinical, laboratory, neurophysiological and neurogenetic assessment. Median age at symptom onset was 52.1 years, and men and women were equally affected. Patients presented with hemifacial or bilateral facial paresthesia and weakness, which evolved with dysphagia, dysphonia, and facial and tongue atrophy and, finally, a dropped-head, upper limb weakness and syringomyelia-like sensory disturbances in the upper limbs. All 10 patients showed chronic diffuse neurogenic compromise of bulbar, cervical and thoracic myotomes, and abnormal blink reflex tests. A positive family history of neurodegeneration was identified in six cases, and revealed pathogenic gene variants in three families (involving VCP, TARDBP and CHCHD10). Thus, our case series has revealed new findings regarding FOSMN syndrome: (i) its clinical course is not always benign, with poorer prognoses associated with dropped-head syndrome and early bulbar compromise; (ii) FOSMN syndrome may be part of a complex familial neurodegenerative spectrum; and (iii) a definite genetic basis may be observed in some cases.

Familial progressive bilateral facial paralysis in Finnish type hereditary amyloidosis

A 60-year-old Brazilian man gave a 20-year history of progressive bilateral facial weakness. He was known to have lattice corneal dystrophy. His father, two paternal uncles and a son had similar neurological problems. His father was born in Portugal and his paternal grandmother was born in Finland. On examination, there was severe bilateral facial weakness (figure 1). Neurophysiology studies found bilateral axonal facial neuropathy but …

Collagen type VI-related myopathy

A 15-year-old Brazilian boy presented with slowly progressive infancy-onset global amyotrophy and limb-girdle pattern of weakness. His perinatal history and prior motor milestones were normal, and there was no relevant family history. On examination, he had a scoliosis, multiple joint contractures with distal hypermobility, follicular hyperkeratosis and keloid scar formation (figure 1). Figure 1 Examination findings in collagen type VI-related myopathies. (A) Marfanoid habitus and marked proximal and distal upper limb muscle atrophy with multiple …

Early-onset axonal Charcot-Marie-Tooth disease due to SACS mutation

Axonal Charcot-Marie-Tooth disease (CMT) represents an expanding group of inherited motor and sensory neuropathies in clinical practice. SACS-gene related disorders have been associated with complex neurological phenotypes of early-onset cerebellar ataxia, spastic-ataxia, spastic paraplegia, demyelinating neuropathy and variable ophthalmological, cognitive and psychiatric disturbances, but never related to pure axonal neuropathy phenotypes. Two unrelated Brazilian men with early-onset axonal CMT-like presentations associated with SACS gene mutations are presented. Both patients presented with pure sensorimotor axonal neuropathy without cerebellar ataxia, spastic paraplegia or other systemic and neurological involvement. Classical neuroimaging findings observed in other sacsinopathies were observed in both cases. Homozygous pathogenic mutations were found in SACS gene in both patients. SACS gene mutations can be associated with pure axonal sensorimotor neuropathy without other neurological features, but with typical neuroimaging features of other sacsinopathies, disclosing the importance of performing neuroimaging studies in patients with suspected axonal CMT.

Teaching Neuro Images : Early-onset dementia and demyelinating neuropathy disclosing cerebrotendinous xanthomatosis

A 40-year-old woman presented with a 5-year history of numbness in hands and feet, apathy, compulsive behavior, and aggression towards others. Medical history disclosed juvenile-onset cataracts. Examination disclosed tendinous xanthoma. Electroneuromyography disclosed sensorimotor demyelinating polyneuropathy. Neuroimaging studies showed global cortical atrophy. Tc-99m brain SPECT scan showed marked hypoperfusion involving the frontal and temporal lobes (figure). Plasma cholestanol levels and bile alcohol glycoconjugates were elevated, enabling a diagnosis of cerebrotendinous xanthomatosis (CTX).

Teaching Neuro Images : MR neurography for the diagnosis of hypertrophic neuropathies

A 25-year-old woman presented with a 10-year history of frequent falls and deafness. Her mother had a similar neurologic picture. Examination showed peroneal amyotrophy, pes cavus, and hearing loss. Magnetic resonance (MR) neurography showed diffuse nerve enlargement in the lower limbs (figure). Genetic analysis revealed heterozygous mutation c.82T>C (p.Trp28Arg) in the PMP22 gene, defining diagnosis of Charcot-Marie-Tooth disease (CMT) type 1A.

New genetic causes for complex hereditary spastic paraplegia

INTRODUCTION Hereditary Spastic Paraplegia (HSP) represents a complex and heterogeneous group of rare neurodegenerative disorders that share a common clinical feature of weakness and lower limb spasticity that can occur alone or in combination with a constellation of other neurological or systemic signs and symptoms. Although the core clinical feature of weakness and lower limb spasticity is virtually universal, the genetic heterogeneity is almost uncountable with more than 70 genetic forms described so far. We performed review of medical records from twenty-one patients from seventeen Brazilian families with complex phenotype of HSP. All cases have previously negative mutations in SPG11/KIAA1840 and SPG7 gene and were evaluated by whole-exome sequencing. An extensive description of systemic and neurological signs has been described. RESULTS Whole-exome sequencing was unremarkable in eight patients and established a definite genetic diagnosis in thirteen patients of twelve non-related families. Mutations were found in genes previously implicated in other neurodegenerative disorders such as Amyotrophic Lateral Sclerosis, Hereditary Neuropathy, Spastic Ataxias, Neurodegeneration with Brain Iron Accumulation, Glycogen Metabolism, Congenital Lipodystrophy and aminoacyl-tRNA synthetases disorders. CONCLUSIONS We report thirteen new genetically-proven cases of complex HSP, expanding the clinical spectrum of presentations of HSP, providing new pathophysiological mechanisms and disclosing new potential therapeutic targets.

NFU1-Related Disorders as Key Differential Diagnosis of Cavitating Leukoencephalopathy

Genetic leukoencephalopathies represent an expanding group of inherited disorders associated with involvement of brain white matter. Cystic degeneration has been previously described with some acquired or inherited leukoencephalopathies. We describe a 6-month-old Brazilian boy with a 2-month history of severe and rapidly progressive developmental and psychomotor regression and seizures. Neurological examination showed spastic tetraparesis and lethargy. Neuroimaging showed diffuse and symmetric cavitating cystic leukoencephalopathy. Whole-exome sequencing revealed compound heterozygous mutations in the NFU1 gene, providing definite genetic diagnosis of multiple mitochondrial dysfunction syndrome type 1. We report a rare presentation of early-onset cystic leukoencephalopathy in the context of multiple mitochondrial dysfunction syndrome type 1.

Infantile-onset ascending spastic paraplegia phenotype associated with SPAST mutation

Infantile-onset ascending spastic paralysis (IAHSP) (OMIM #607225) represents an extremely rare autosomal recessive neurodegenerative disorder characterized by very early onset spastic paraplegia with an ascending phenotype with quadriplegia and bulbar involvement in late stage due to ALS2mutations [1].We describe a Brazilian patientwith the IAHSP phenotype related to heterozygousmutation in the SPAST gene that have never been described in the literature in association with such phenotype. A 36-year-old Brazilian woman presented with regression of her motor milestones during her second year of life with weakness, lower limbs spasticity and frequent falls, evolving with severe spasticity in the upper limbs, mild dysphagia, severe dysarthria and becoming wheelchair-bound at 6-year-old. Medical history disclosed unremarkable pregnancy and neonatal periods without events suggestive of possible hypoxic-ischemic encephalopathy. Cognitive profile and memory function were preserved. Family history was unremarkable. Examination showed severe spastic tetraparesis with lower limb deep sensory loss, global brisk tendon reflexes with extensor plantar responses, bilateral ankle clonus, bilateral pes cavus, slow saccadic eyemovements and spastic anarthria. Motor-evoked potentials were profoundly affected with marked delayed responses. Nerve conduction studies and electromyogram were almost normal. Neuroimaging showed bilateral corticospinal tract hyperintensities in FLAIR and T2-weighted sequences (Fig. 1). Serum cobalamin, copper dosage, serological tests for HIV, CMV, EBV, HSV-I/II, Varicella Zoster, Brucella, Treponema pallidum and Borrelia burgdorferiwere normal. Cerebrospinal fluid analysis (including polymerase-chain reaction for CMV, EBV and HSV-I/II virus), VDRL and search for malignant neoplasm cells were unremarkable. Wholeexome sequencing revealed a previously reported heterozygous missense pathogenic mutation c.1496GNA [2] resulting in p.Arg499His in the SPAST gene (2p22.3), which causes Hereditary Spastic Paraplegia type 4 (SPG4). Hereditary Spastic Paraplegia (HSP) comprises a heterogenous group of rare inherited neurodegenerative disorders characterized by lower limb spasticity and weakness resulting from primary retrograde dysfunction of the long descending fibers of the corticospinal tract due to impairment of membrane vesicular trafficking, organelle morphogenesis, axonal transport, lipid metabolism, mitochondrial functions