Hypotonia, neuropathies and myopathies

Aims Able to take a history to work out if has neuromuscular problem Know some of the common causes of hypotonia, neuropathies and myopathies Able to think about relevant investigations

Reasons for referral Delay in motor milestones Abnormal gait Tendancy to fall Overt muscle weakness, floppiness or hypotonia Muscle cramps Muscle stiffness

Why make a diagnosis Parental request Disease specific treatment Disease specific complications Prognostication Genetic counselling Antenatal diagnosis

History Presenting complaints Onset Progression Developmental milestones Systems inquiry Family history

Clinical examination- establishing the phenotype ptosis/opthalmoplegia/facial weakness/tongue fasiculation Muscle size Hypotonia/myotonia Functional strength Muscle weakness prox vs distal, arms vs legs, axial Contractures-limbs/spine Resp pattern Muscle enlargement/atrophy

Where is the lesion Muscle bulk Tone Strength DTR Plantars sensation fasicualtion UMN N  - Ant horn cell Prox wasting  Prox weakness  + P nerve Distal wasting Distal weakness Distal  rarely NMJ fatigues N-  selective

Investigations Blood Radiological Neurophysiological Other CK elevated in Musc dystrophies, metabolic and inflamm myopathies, carriers of DMD, hypothyroidism,hyperCKaemia,malignant hyperthermia, healthy individuals after excessive exercise Myasthaenia=tensilon Skeletal-xray hips/spine Resp Cardiac swallow

Floppy infant Looks floppy Feels floppy Increased joint mobility

Hypotonia With weakness Without weakness Neuromuscular disorders CNS Metabolic Chromosomal Connective tissue How can you tell whether weak= antigravity mvmts, resistance on pull to sit

Hypotonia With weakness Without weakness Neuromuscular disorders CNS SMA Congenital myotonic dystrophy Myotubular myopathy Congenital muscular dystrophy Without weakness CNS Birth asphyxia/hypoxia CNS malformations Metabolic Lipidoses/mucopolysaccharidoses Amino/organic acidurias Chromosomal Down syndrome Prader-Willi syndrome Connective tissue Ehlers Danlos/Marfans Osteogenesis Imperfecta How can you tell whether weak= antigravity mvmts, resistance on pull to sit

? When do we think of SMA? Child with hypotonia and weakness The weakness is usually symmetrical and more proximal than distal. Sensation is preserved. Weakness in the legs is greater than in the arms. Severity of weakness generally correlates with the age of onset The most severe type presents in infancy. The infant may appear normal at birth. Weakness evolves within the first few months of life. Occasionally, decreased intrauterine movements suggest prenatal onset of the disease and present with severe weakness and joint contractures at birth.6 Milder types of spinal muscular atrophy present with later onset, and the course is more insidious. Some children sit but never walk, whereas others show delayed walking but may be able to maintain walking until adult years. For the purpose of clinical care and discussion, individuals manifesting different levels of weakness due to spinal muscular atrophy have been divided into 4 groups defined by functional ability

Clinical Spectrum Type I Type II Type III 6 months 18 months 5 years Werdnig Hoffman Hypotonia /floppy weakness/wasting breathing / feeding difficulties Absent reflexes Death < 2 years Type II Sit unaided, not standing Tremor affecting upper limbs Prognosis dependent on chest Type III Independent walking with proximal weakness 6 months 18 months 5 years Age at Presentation

Genetics Autosomal recessive Carrier frequency 1 in 40 in general population Due to loss of function of SMN1 (survival motor neurone 1) Gene located on Cr 5 is the Survival Motor Neurone gene SMN gene has 9 exons & encodes a protein found in all cells but most abundantly in the nucleus of the motor nerve 93% of patients with SMA are missing exon 7 in both copies of the SMN gene. A further 5% are missing exon 7 in one copy and have a rearrangement in the other copy 2% have rearrangements and will not be picked up on routine genetic testing SMN2 produces only 10% full length SMN protein predicting clinical phenotype using SMN2 copy number can be risky and is not currently recommended. Cannot easily determine smn 2 copy number

Duchenne muscular dystrophy

Clinical presentation Age within first 5 years of age Delayed motor milestones esp walking 50% 18 months 25% 2 years Abnormal gait ( toe walking, waddling) Frequent falls Other motor difficulties Speech and language delay Global delay

Gowers manoeuvre

Cardinal clinical signs Broad based waddling gait, lordotic posture Inability to run,jump or hop normally Positive Gowers Prox musc weakness legs> arms Prominence of calves

X linked recessive; mutation in dystrophin gene located at Xp21 1:3500 births X linked recessive; mutation in dystrophin gene located at Xp21 Diagnosis Clinical assessment Molecular genetic testing Picks up 60-65% deletions Duplications in 5-15% Rest point mutations/intronic rearrangements Dystrophin expression on muscle biopsy

What is a neuropathy Disease in which the peripheral nerve is damaged Acquired or genetic Axonal or demyelinating Polyneuropathy,focal or multifocal Motor,sensory,sensorimotor or autonomic

HMSN type 1

Slowly progressive distal neuropathy Onset childhood-adulthood Progressive distal atrophy and weakness Pes cavus Sensory loss later Motor and sensory conduction very slow

AD 1A duplication/point mutation of PMP 22 gene on chromosome 17p11.2 1B: point mutation of protein zero gene on 1q22 More loci as well

Summary Think about where lesion is likely to be based on history and examination THEN make appropriate investigations

Any questions???