Yadollah Harati, M.D., F.A.C.P. A 34 year old male with predominantly distal weakness, atrophy and myotonia Cecile L. Phan, M.D., F.R.C.P.C. Eddie L. Patton, M.D. Yadollah Harati, M.D., F.A.C.P.

Clinical History 34 yo RHD male presented with complaint of muscle atrophy and weakness affecting the hands and feet. Onset unclear. Probably had symptoms for years but never interfered with daily activities. Progression very slow and insidious. January 2009: Difficulty putting on sandals because he could not lift the toes. Bilateral foot drop Hand grip weaker, hand muscles are atrophied

Clinical History Recently had difficulty fully lifting the legs up to put on socks. No ocular, facial, bulbar, or respiratory symptoms. No muscle twitches, cramps, difficulty releasing hand grips, or sensory abnormalities. No cognitive complaints

Clinical history Evaluated by local neurologist who performed EMG/NCS which showed a moderate-severe myopathy with fibrillations and positive sharp waves. He was referred to us for consultation and a muscle biopsy to rule out an inflammatory myopathy or a glycogen storage myopathy

Clinical History PMHx and SHx: Medications: Allergies: Normal development in childhood and adolescence, although never been involved much in sports. Exercise induced asthma Vitamin B12 deficiency – has been on B12 injections without any improvement in symptoms. Right wrist surgery Medications: None Allergies:

Clinical History Social Hx: Family history: ROS: Computer specialist. Married, has twin daughters Drinks and smokes socially Family history: Parents still alive 3 sisters, 1 brother. One sister has B12 deficiency. Twin daughters healthy. French Cajun origin. No other extended family members with similar symptoms. ROS: Negative

Physical examination General examination unremarkable Neurologic exam: Normal cognitive function Cranial nerves were normal Symmetrical wasting of the proximal arm muscles, paraspinal muscles, intrinsic muscles of the hands and feet, and anterior compartment of the legs.

Neurologic examination Right Left Neck flexors 5 Neck extensors Deltoids External rotators 4 Biceps Brachioradialis Triceps Wrist extensors 4+ Wrist flexors Finger extensors Finger flexors 5- Interossei Thenar Right Left Iliopsoas 4 Hip adductors 4+ Hip abductors Quadriceps 5 Hamstring Tibialis anterior 1 Extensor Hallucis L. Peronei Tibialis posterior Gastrocnemius

Neurologic exam Sensory exam – normal Right Left Biceps Brachioradialis Triceps Patella +2 Achilles Plantar resp Down Sensory exam – normal Gait and balance – bilateral foot drop Remaining neurologic exam normal

Investigations: EMG/NCS of the right UE and LE: NCS shows low CMAP amplitude secondary to atrophy with normal dML and CV. EMG shows diffuse short duration, polyphasic units with evidence of myotonia in several muscles, distal > proximal. Myopathic abnormalities were also noted in the paraspinous and sternocleidomastoid muscles.

Investigations CPK 411 U/L Genetic testing for myotonic dystrophy type I negative Right biceps muscle biopsy was performed.

H&E: Marked increased variability in fiber size and shape H&E: Marked increased variability in fiber size and shape. Most fibers appear rounded. Clusters of rounded, small fibers as well as hypertrophic fibers (up to 152 microns) are seen. Increased endomysial connective tissue is also observed.

H&E: several fibers contain one or several rimmed vacuoles

H&E: rimmed vacuole with granular material lining the vacuole

ATPase 9. 4: atrophic and hypertrophic fibers of both fiber types ATPase 9.4: atrophic and hypertrophic fibers of both fiber types. The vacuoles are often seen in clusters of atrophic fibers.

NADH (left) and non-specific esterase (right): atrophic, angular fibers with excessive NADH and non-specific esterase activity indicative of neurogenic atrophy

SMI 31: SMI 31 positive aggregates seen in the cytoplasm of a non-vacuolated fiber (arrow, left figure) and diffuse increase in the cytoplasm of some atrophic fibers (right figure

Summary A 34 year old male with a few years history of insidious onset and slowly progressive muscle atrophy and weakness affecting initially the distal followed by proximal muscles in the arms and legs. EMG/NCS showed a generalized myopathy with myotonia Biopsy showed a moderately severe, chronic, non-inflammatory myopathy with abundant rimmed vacuoles, SMI 31 positive aggregates, rare congophilic deposits, and mild neurogenic atrophy.

DDx of muscle disorders with rimmed vacuoles: Inclusion body myositis Hereditary inclusion body myopathy: h-IBM1 (desmin myofibrillar myopathy) h-IBM2 (Nonaka distal myopathy) h-IBM3 (myosin heavy chain IIa) h-IBM with Paget disease and frontotemporal dementia (IBMPDFTD) Distal myopathies/muscular dystrophies: Early adult onset – Gowers-Laing, Miyoshi Late adult onset – Welander, Markesbery-Griggs, Udd Myofibrillar myopathies Others: OPMD Oculopharyngodistal myopathy Pompe, Danon Emery-Dreifuss X linked LGMD 1A, 1G, 2G X-linked myopathy with excessive autophagy

A diagnostic test was performed… What is the diagnosis?

Genetic testing for Inclusion Body Myopathy via GNE gene sequencing: Homozygous mutation in exon 10 of the GNE gene  substitution of isoleucine by threonine at codon 618 (p.Ile618Thr) This mutation has been found in 2 families, one originating from a French Cajun family in Louisiana, and another from Italy.

Hereditary Inclusion Body Myopathy type 2 (h-IBM2 OMIM#600737) Final diagnosis Hereditary Inclusion Body Myopathy type 2 (h-IBM2 OMIM#600737)

h-IBM2 The term “hereditary inclusion body myopathy” refers to several syndromes with AD or AR inheritance. Most common form (h-IBM2) was originally described in Persian Jewish families Patients from other ethnicities have been identified (Caucasian, Indian, Thai, Japanese, African)

h-IBM2 Clinical course: onset in 2nd-3rd decade of life weakness and atrophy of distal lower limbs followed by proximal progression Partial or complete sparing of quadriceps even in advanced stage Upper limbs – shoulder girdle, wrist extensors, hands affected in more advanced stage Progression of muscle weakness continues over the next 10-20 years after onset Usually spares ocular, bulbar, and respiratory muscles. Cardiac involvement in rare, severe cases.

h-IBM2 Investigations: CPK normal or mildly elevated (2-5X) EMG/NCS: Myopathic changes Spontaneous activity fibs, PSW, CRD ? Myotonia (recent case report* of patient with IBMPFD –hereditary IBM with Paget’s disease and frontotemporal dementia – also showed myotonic discharges) MRI – fatty replacement of muscles (early – anterior tibialis, hamstring; later – gastrocnemius) *Barohn RJ, Watts GD, Amato AA. A case of late onset proximal and distal muscle weakness. Neurology 2009; 73 (19):1592-1597

h-IBM2 Pathology: Chronic myopathic changes Rimmed vacuoles Protein aggregates: SMI 31 positive hyperphosphorylated tau aggregates βAPP, ubiquitin, ApoE Intracytoplasmic and intranuclear tubulofilamentous inclusions on EM Variable degree of neurogenic atrophy Occasional congophilic deposits Usually lack inflammation

h-IBM2 Molecular Genetics: Autosomal Recessive inheritance Gene encoding GNE, chromosome 9: Over 60 mutations described world wide Usually missense mutations

GNE function: GNE Sialic acid is present on distal ends of N- and O-glycans and involved in many biological functions

h-IBM2 Role of GNE in the pathogenesis of hIBM2: Hypothesis: Impaired GNE function  hyposialylation of important muscle glycoproteins such as α dystroglycan and NCAM perturbed folding and trafficking through ER and Golgi apparatus  accumulation of these abnormal proteins in cytoplasm  activating ubiquitin-proteosome system or the autophagic process  progressive muscle fiber degeneration.

h-IBM2 Treatment: BMC Neurology 2007, 7:3

h-IBM2 treatment 4 h-IBM2 patients were treated with IVIg because IVIg contains 8μmol of sialic acid/g Loading dose 1g/kg X 2 consecutive days followed by 400 mg/kg q weekly X 3 weeks Results: Quadriceps strength improved by 22% after loading dose and 35% at end of study Shoulder abduction improved by 44% after loading dose and 46% at end of study Composite improvement for 8 other muscle groups were 5% after loading dose and 19% at end of study. Patients experienced subjective improvement in daily activities No evidence of increased sialylation on α dystroglycan and NCAM in muscle samples after IVIg treatment.

h-IBM2 treatment Use of sialic acid precursors such as Man-NAc could be a source of sialic acid. Human Man-NAc trial is currently on hold because of a lack of funding to complete animal toxicity trials

Conclusions h-IBM is a very rare disease! However, the striking histopathologic similarities between h-IBM and Inclusion Body Myositis suggest that they share downstream pathologic mechanisms that lead to progressive muscle fibers degeneration. The pathogenesis of this disease and the role of GNE is still unclear. Sialylation abnormalities may be epiphenomena and GNE mutation could affect cellular functions unrelated to sialic acid pathway.