Case: Bolino Proband 3, reported at 14yo, symptom onset at 4yo

CasePresentingHPOs: HP:0009053, HP:0008959, HP:0007181, HP:0009049, HP:0001284, HP:0010871, HP:0001337, HP:0001761, HP:0001765, HP:0012447, HP:0003383 (distal lower limb muscle weakness, distal upper limb muscle weakness, interosseous muscle atrophy, peroneal muscle atrophy, absent tendon reflexes, sensory ataxia, tremor, pes cavus, hammertoe, abnormal myelination, onion bulb formation)

HPOsFreeText: interosseous muscle weakness, normal psychomotor development, sensory ataxia noted with tremor, normal autonomic function and superficial sensations, unremarkable general examination, routine laboratory tests normal, CSF exam normal, CMAPS absent from peroneal and median nerves, SNAPs absent from sural nerves. Light microscopy showed irregularities and outfoldings of myelin sheath

CountryOrigin: Italy

FamilyInfo: non-consanguineous parents

PreviouslyPublished: 10673338, 8195799

GenotypingMethod: PCR of genomic DNA, establishment of MTMR2 genomic structure, cDNA sequence aligned with partial genomic sequence from PAC clone CMB9-9116, available family members analyzed and segregation of variant with disease confirmed in pedigree

Variant: NM_016156.5(MTMR2):c.1444C>T (p.Gln482Ter), homozygous

ClinVar: 6234, https://www.ncbi.nlm.nih.gov/clinvar/variation/6234/

gnomAD: 0.000003988, https://gnomad.broadinstitute.org/variant/11-95574816-G-A

Case: Bolino Proband 2 (Case 25 in PMID:10677858), female, reported at 5yo, symptom onset at 2yo

CasePresentingHPOs: HP:0001270, HP:0030319, HP:0008959, HP:0008994, HP:0009053, HP:0002522, HP:0003474, HP:0000218, HP:0001761, HP:0003447, HP:0012447 (motor delay, facial weakeness, distal upper limb muscle weakness, proximal lower limb muscle weakness, distal lower limb muscle weakness, lower limb areflexia, sensory impairment, high palate, pes cavus, axonal loss, abnormal myelination)

HPOsFreeText: walked at 17mo, tendon reflexes absent in lower limbs but present in upper limbs, sensory action potential absent in all nerves tested , CMAPs had small amplitude and temporal dispersion in upper limbs and were not detectable in lower limbs, EMG of tibialis anterior showed neurogenic features, presence of myelin loops and excessive outfolding, thick and irregular myelin sheaths

NotHPOs: HP:0003383 (onion bulb formation)

CountryOrigin: Saudi Arabia

PreviouslyPublished: 10677858

FamilyInfo: consanguineous family

GenotypingMethod: RT-PCR of RNA from patient lymphoblastoid cell line, available family members analyzed and segregation of variant with disease confirmed in pedigree

Variant 1: NM_003912.1:c.1480_1593del

ClinVar: 637472, https://www.ncbi.nlm.nih.gov/clinvar/variation/637472/

gnomAD: absent

Variant 2: NM_016156.5(MTMR2):c.826G>T (p.Glu276Ter)

ClinVar: 6233, https://www.ncbi.nlm.nih.gov/clinvar/variation/6233/

gnomAD: absent

ScoringNotes: both variants stated to be homozygous on same allele, assume variants in trans

Case: Bolino Proband 1 (proband 1945), male, reported at 4yo, symptom onset at 42mo

CasePresentingHPOs: HP:0001349, HP:0003701, HP:0001284, HP:0001288, HP:0003474, HP:0003693, HP:0003722, HP:0003391, HP:0001761, HP:0003383, HP:0012447 (bilateral facial weakness, proximal muscle weakness, areflexia, abnormal gait, sensory impairment, distal limb muscle atrophy, neck flexor weakness, Gower's sign, pes cavus, onion bulb formation, abnormal myelination)

HPOsFreeText: walked at 14mo, eyes reported to be normal, gait - bilateral steppage, pes equinovarus deformity of both feet, frequent falling, had normal early motor milestones, bilateral pes cavus with retraction of Achille's tendon, intellectually normal. Laboratory testing normal: full blood count, fasting blood glucose, serum electrolytes, creatine kinase, lactic acid, urinary organic acids, serum and urine carnitine, EEG, ECG, and liver echography, segmental demyelination in 92% of fibers, redundant loops of myelin sheath irregularly arrayed near axon, muscle biopsy of rectus femoris showed atrophic and angulated fibers in clusters and large type grouping, lipid accumulation

Median nerve conduction studies: compound motor action potential = 4.6uV, distal motor latency = 7.8msec, sensory action potential = 3.3uV, motor nerve conduction velocity = 17msec, sensory nerve conduction velocity = 18msec

Peroneal nerve conduction studies: compound motor action potential = 0.21uV, distal motor latency = 7.8msec, motor nerve conduction velocity = 14

Sural nerve conduction studies: sensory action potential = no response, sensory nerve conduction velocity = no response

CountryOrigin: Italy

FamilyInfo: consanguineous family, parents reported to be normal at clinical and electrophysiological exams

PreviouslyPublished: PMID:10673338, PMID:8817346, PMID: 8628474, PMID: 8017168

GenotypingMethod: RT-PCR of RNA from patient lymphoblastoid cell line, available family members analyzed and segregation of variant with disease confirmed in pedigree - PMID:8817346 - homozygosity mapping and haplotype sharing through microsatellite and linkage analysis

Variant: NM_016156.5(MTMR2):c.1276C>T (p.Gln426Ter) homozygous

ClinVar: 6231, https://www.ncbi.nlm.nih.gov/clinvar/variation/6231/

gnomAD: 0.000007085, https://gnomad.broadinstitute.org/variant/11-95578227-G-A