MPZ mutations associated with deafness and abnormal pupillar

reaction in Czech CMT2 patients, but also in HMSN III patients.

P. Seeman 1, K. Huehne 2, R. Mazanec 3, B. Rautenstrauss 2, V. Beneš jr.1, P. Šušlíková1, O. Keller 4.

1- Dept of Child Neurology, 3 - Dept of Neurology 2nd School of Medicine, Charles University Prague, 2- Institute of Human

Genetics, University Erlangen, 4- Dept of Neurology Thomayer University Hospital Prague.

Different HMSN phenotypes associated with MPZ mutations.

• Charcot – Marie – Tooth type 1B (demyelinating)

• Dejerine – Sottas neuropathy (DSN)

• Congenital hypomyelination neuropathy (CHN)

• Charcot – Marie – Tooth type 2 (axonal) - „new“

Deafness in CMT

• Deafness was reported in some of the CMT2 families with MPZ mutations (Thr124Met)

• Deafness was not observed in HMSN type III patients or families associated with MPZ mutations

Myelin protein zero (MPZ).

173bp

307bp

307bp

278bp

309bp

exon 1 exon 2 exon 3 exon 4 exon 5

Myelin protein zero gene.

exon 6

Axonal - CMT 2 phenotype due to mutation in myelin gene (MPZ).

Recent findings of MPZ mutations in CMT2 patients and families with distinct phenotype(Ser44Phe, Asp61Gly, Asp75Val, Ile99Thr, Tyr119Cys, Thr124Met, Gln141stop, …)

• axonal type of CMT - EMG and nerve biopsy

• late onset polyneuropathy

• abnormal pupillar reaction – slow or absent

• deafness - usually after the onset of neuropathy

Czech family with axonal CMT beginning with deafness

Family F.

Family F.• hearing loss and deafness as the first symptom of CMT

disease - at the late teens in the grandfather and in the mother - progressive hearing loss, deaffness now

• abnormal pupillar reaction (Argyll-Robertson pupilles, Adie pupilles) before the onset of the neuropathy

• fully normal fysical abilities untill the end of 3rd decade• late onset of polyneuropathy of axonal type - slow

progression at the grandfather but quite fast at the mother, 12 years old boy clinically still unaffected

• severe distal muscle atrophies in mother and grandfather• whorsening of electrophysiological findings correlated

with higher age in the family – axonal loss and later demyelination

distal atrophies and weakness

no pes cavus, severe footdrop

pronounced hand muscles atrophies

Electrophysiological (EMG, VEP, BAEP) findings I.

Motor and sensory nerve conduction velocities

Patient Motor nerve Sensory nerve

DML CMAP MCV SCV SNAP

(ms) (mV) (m/s) (m/s) (uV)

645 Tibial none Sural none

Grandf. Median 9.4 0.1 29 Median none

622 Tibial none Sural none

moth) Median 4.8 0.4 30 Median 14 7

623 Tibial 6.2 10.3 40 Sural 47 16

boy) Median 3.5 13.2 45 Median 47 26

Electrophysiological (EMG, VEP, BAEP) findings II.

Brainstem auditory evoked potentials (monoaural,rarefaction click, 10 Hz )

Patient Side Latencies of waves /ms/

I III V  I-III III-V I-V645 L no responseG R no response

622 L 2.36 4.44 6.29 2.08 1.85 3.93 M R 2.30 4.32 none 2.02 none none

623 L 1.68 3.92 5.58 2.24 1.66 3.90B R 1.98 4.15 6.11 2.17 1.96 4.13

Upper limits of normal range of BAEPs in our laboratory / +- 2 SD /:Latencies : I 2.04 ms III 4.16 ms V  6.06 ms I – III 2.16 ms III – V 2.04 ms I – V 4.15 ms

Electrophysiological (EMG, VEP, BAEP) findings III.

Visually evoked potentials (pattern reversed, monocular, 2 Hz, 16 ´´) Latencies of waves / ms /

N 75 P 100 N 145

Patient Side

645 Left 79 104 136

Right 79 105 137

622 L 68 100 127

R 67 100 124

623 L 76 124 189

R 76 116 193

Limits of normal range of VEPs in our laboratory / +- 2 SD /

Latencies : N 75 / 67 – 84 ms / P 100 / 94 – 116 ms / N 145 / 125 – 155 ms /

Amplitude: N 75 / P 100 5.4 uV

Results from the mother (nr. 622)

VEP – normal latencies BAEP – prolonged latencies - peripheralAudiometry – profound perception hearing lossbrain MRI – normal, only diffuse nonspecific white matter changes in both hemispheres CSF – normal protein and normal cell countmuscle biopsy – neurogenic lesion, fiber hypertrophy and atrophynerve biopsy – done in 1993, axonal loss, axonal lesion

290 A>T (Glu97Val) in MPZ gene

Nerve and muscle biopsy in nr. 622 (mother)

Normal control

nerve muscle

MRI in nr. 622 (mother)

MRI in nr. 622 (mother)

Dejerine Sottas neuropathy and MPZ mutation

• Deafness was usually not reported in DSS patients – (but the reported patients were usually children or young persons, few data about adult DSS patiens and their hearing status)

Family K.

• Mutation Arg98Cys - neighbour aminoacid to the previous family

Family K.• Mother (44y.) and son (18y.) severely affected (HMSNIII or

DSN), no other affected members in the family• early onset (3 y.) with hypotonia, delayed motor milestones,

scoliosis, both affected never achieved normal independent gait• distal weakness and atrophies, areflexia, rather nonprogressive

course• extremely decreased MNCV ( 8-10 m/s), absent SNAP• CSF - ?• hypertrofic demyelinating neuropathy (with onion- bulbs) in

the sural nerve biopsy in the mother• in the mother from the age of 25 y. - hearing loss, presently

sensorineural hearing loss bilateral ( up to 70 dB)both affected showed abnormal pupillar reaction - extremely prolonged opening reaction (opening)

Family K.mother son

Family K.mother son

Conclusions• Is deafness a common feature associated with MPZ mutations,

but later in life (in adult age) ?

• Do also other HMSN III or DSN patients develop hearing loss in adulthood ?

• In our CMT2 family F. (Glu97Val), deafness was by far the first symptom of the disease – before any signs of HMSN

• Testing of the functional effect of the newly discovered mutations with CMT2 phenotype in expression systems should clarify the mechanism leading to axonal demage resulting from some MPZ mutation

• Only the location in the extracellular domain alone, do not explain really different phenotypes resulting from mutation of the neibour aminoacids ( Lys96Glu – CMT1, Glu97Val – CMT2, Arg98Cys – DSN, Arg98His - Ile99Thr – CMT2)some other mechanism is more probable.