**7.5.3 Case study 3**

A 68 year-old mother of case 1 and 2. She had the same family history of ALS, with a point mutation in SOD1 gene at val148gly. Her pedigree is shown in Figure 12. She was also asymptomatic at the time of recruitment. Her right and left thenar MUNE's remained stable at around 130 motor units. Due to her age, she was not followed as regularly as her daughters.

On her review in November 2001, there had been a reduction of her right thenar MUNE to 98 (23%) and her left thenar MUNE to 98 (25%), with no detectable weakness. Her right EDB MUNE also dropped from 147 to 106 (28%), but she did not have any detectable weakness. She subsequently developed voice change 6 months later in May 2002, and died of respiratory failure in August 2002. Progress MUNE and handgrip results are shown in Table 6.


Table 6. Case 3 progressive handgrip, dorsiflexion power and thenar and EDB MUNE results

### **7.5.4 Case study 4**

A 48-year-old lady with a strong family history of ALS. This family had a point mutation in SOD1 gene at glu100gly. At the time of recruitment, the subject was asymptomatic, with a normal neurological examination and no evidence of wasting, weakness or fasciculations. Progress MUNE results are shown in Table 7.

The MUNE results remained stable over the first 2½ years of the study. Her right EDB MUNE results remained stable at around 120 motor units. It was then noted that her left EDB MUNE had dropped from 118 to 64 (46% reduction) and her right thenar MUNE had also dropped from 153 to 123 (20% reduction). She did not have any detectable weakness of her upper or lower limbs. Needle EMG showed neurogenic changes, but not sufficient to fulfil the criteria for ALS.

She subsequently developed left lower leg weakness with inversion and eversion of MRC grade 3/5 and dorsiflexion and plantarflexion 4/5, 6 months later. Her disease progressed rapidly and died within the 4 months of diagnosis, in March 2002 of respiratory failure.


Table 7. Case 4 progressive handgrip, dorsiflexion power and thenar and EDB MUNE results

### **7.5.5 Case study 5**

652 Amyotrophic Lateral Sclerosis

extensor carpi radialis longus, bilaterally but no fibrillation potentials were seen. It was felt

In view of her strong family history, a presumed diagnosis of familial ALS was made and

Over the next 3 years, her EDB MUNE results have stabilised. Her weakness has not progressed significantly. In February 2004, she still had MRC grade 4+/5 power of her right dorsiflexors and no symptomatically apparent weakness in her left dorsiflexors or upper

A 68 year-old mother of case 1 and 2. She had the same family history of ALS, with a point mutation in SOD1 gene at val148gly. Her pedigree is shown in Figure 12. She was also asymptomatic at the time of recruitment. Her right and left thenar MUNE's remained stable at around 130 motor units. Due to her age, she was not followed as regularly as her

On her review in November 2001, there had been a reduction of her right thenar MUNE to 98 (23%) and her left thenar MUNE to 98 (25%), with no detectable weakness. Her right EDB MUNE also dropped from 147 to 106 (28%), but she did not have any detectable weakness. She subsequently developed voice change 6 months later in May 2002, and died of respiratory

**weakness 1st detected -43 -41 -38 -6 0 +3 Date of study** Oct-98 Dec-98 Mar-99 Nov-01 May-02 Aug-02 **R Handgrip** 55 55 55 55 Voice Died

failure in August 2002. Progress MUNE and handgrip results are shown in Table 6.

**R Thenar MUNE** 127 135 130 98 Change

Table 6. Case 3 progressive handgrip, dorsiflexion power and thenar and EDB MUNE

A 48-year-old lady with a strong family history of ALS. This family had a point mutation in SOD1 gene at glu100gly. At the time of recruitment, the subject was asymptomatic, with a normal neurological examination and no evidence of wasting, weakness or fasciculations.

The MUNE results remained stable over the first 2½ years of the study. Her right EDB MUNE results remained stable at around 120 motor units. It was then noted that her left EDB MUNE had dropped from 118 to 64 (46% reduction) and her right thenar MUNE had also dropped from 153 to 123 (20% reduction). She did not have any detectable weakness of her upper or lower limbs. Needle EMG showed neurogenic changes, but not sufficient to

**L Handgrip** 60 50 50 45 **L Thenar MUNE** 130 125 **R EDB power** 5/5 5/5 5/5 5/5 **R EDB MUNE** 147 153 150 106

that these changes were not enough to make the diagnosis of ALS.

she was commenced on Riluzole in February 2002.

limbs.

daughters.

results

**7.5.4 Case study 4** 

fulfil the criteria for ALS.

Progress MUNE results are shown in Table 7.

**7.5.3 Case study 3** 

**Months pre and post** 

A 44-year-old man with a strong family history of ALS and a 2nd cousin once removed of case 4. His family also had a point mutation in SOD1 gene at glu100gly. At the time of recruitment, the subject was asymptomatic, with a normal neurological examination and no wasting, weakness or fasciculations. Progress MUNE results are shown in Table 8.


Table 8. Case 5 progressive handgrip, dorsiflexion power and thenar and EDB MUNE results

The MUNE results remained stable over the first 3 years of the study. The right EDB MUNE dropped from 115 down to being not recordable. Thenar MUNE remained stable at about 130 motor units. He had occasional fasciculations in the right quadriceps region, weakness of the right quadriceps and MRC grade 0/5 weakness of right dorsiflexion. He was unsure

Protection of Motor Neurons in Pre-Symptomatic Individuals Carrying

weakness.

imply that symptoms were imminent.

(Aggarwal & Nicholson, 2002).

months and died of respiratory failure.

SOD 1 Mutations: Results of Motor Unit Number Estimation (MUNE) Electrophysiology 655

change systematically in ALS patients when used by experienced technicians, even though evaluator bias needs to be taken into account. Shefner demonstrated that the statistical MUNE was unreliable in the presence of clinical weakness due to motor unit instability. The difference is that our study was performed on asymptomatic patients, without clinical

It also showed that MUNE may be used as a reliable method of pre-symptomatic detection of motor unit loss in SOD1 mutation carriers. Following 69 SOD1 family members and population controls over a 1-year period, with thenar and EDB MUNE tests repeated every 3 to 6 months, assessed the test-retest reproducibility of the technique. The mean difference between thenar MUNE results on separate occasions in asymptomatic subjects was +/- 3.6%, with a range of 0-11.7%, and +/- 4.6%, with a range of 0-15.7% in EDB MUNE. These results indicate that the reproducibility of this technique and the results achieved was high, so that individual results could be used as a baseline for serial MUNE studies. (Aggarwal, 2009). During the course of the study, however, a significant fall in motor unit number was detected in 5 of the SOD1 mutation carriers, several months before the onset of weakness and the diagnosis of motor neurone disease (MND) being made. There was no detectable loss of motor units in the other 15 SOD1 mutation carriers or in the group of SOD1 mutation negative relatives. From the study, a threshold MUNE of less than 100 was considered to

In individual cases, there was a reduction of 68% 8 months prior, 51% 4 months prior, 46% 6 months prior, 35% 10 months prior and 28% 6 months prior to the onset of weakness. Further motor unit loss occurred as weakness progressed and the diagnosis of MND being made. Case 1 was a 48-year-old lady from a family with a strong history of familial MND, with a point mutation in the SOD1 gene at val148gly. At the time of recruitment in October 1998, she was asymptomatic. Her MUNE results remained stable over the first 2½ years, after which her left EDB MUNE dropped by 51%, and she only had detectable weakness of her left foot 4 months later with wasting and weakness of the anterior compartment muscles of her left leg of MRC grade 2-3/5. Over the next 6 months, her right EDB MUNE dropped by

Her 43-year-old sister also showed a reduction in MUNE prior to the onset of symptoms. About 3 years into the study, there was a reduction in her right thenar MUNE to 96 (20%) and her left thenar MUNE to 89 (19%), with no detectable weakness. Her right EDB MUNE also dropped by 17%, but she only had detectable weakness 10 months later of MRC grade 4+/5 in right dorsiflexors, at which time her right EDB MUNE had dropped by a total of 35%. In view of her strong family history, a presumed diagnosis of MND was made and she was commenced on Riluzole in February 2002. Over the last 2 years, her EDB MUNE have not shown any decline. Her weakness has not progressed significantly, as on her last review in February 2004, she still had MRC grade 4/5 power of her right dorsiflexors and no clinically apparent weakness in her left dorsiflexors or upper limbs. It is possible that since "treatment" was commenced prior to the loss of a significant number of motor neurones, this may have slowed down the progression of the disease in this individual case.

Her mother also had a detectable reduction right thenar MUNE of 23% and left thenar MUNE of 25%, with no clinically apparent weakness. Her right EDB MUNE also dropped by 28%, with no detectable weakness. She subsequently developed bulbar symptoms 6

56%, but she only developed right foot weakness 3 months later in June2001.

as to when weakness developed. Needle EMG showed changes of active and chronic denervation limited to the right quadriceps muscle, which was not considered diagnostic for ALS.

Over the next 6 months, there was a reduction of the left EDB MUNE as well from 114 to 36 (68% reduction), but with no detectable weakness. In July 2002, 8 months later, he was reviewed by his neurologist and was found to have only slightly reduced left ankle power with MRC grade 4/5 and weakness of knee flexion bilaterally. He progressed rapidly after that and by October 2002 had bilateral lower limb weakness to a point were he was unable to stand without assistance and became wheelchair bound. He commenced Riluzole, in May 2003, but over the next year there was progression of upper limb weakness. Currently, his forced lung capacity is around 30% and he is using BiPAP ventilation at night and receives PEG feeding.
