Table 2.
Mutation frequency, mode of transmission, age of onset and neurophysiological features (n=67 kindreds)
| NEFL amino acid change |
Exon | Domain | Subdomain | Kindreds, n (%) |
Familial cases,† n |
Individual cases, n |
Confirmed inheritance patterns‡ |
De novo mutation, n (cases) |
AOO, range (decade) |
AOO ≤3 years, n (cases) |
Median MNCV, range (m/s) |
Ulnar MNCV, range (m/s) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| P8L | 1 | Head | – | 2 (3) | – | 2 | SP | 1 | 1 | 1 | 13–33 | 19 |
| P8Q | 1 | Head | – | 1 (1.5) | 1 | – | – | – | 1 | – | 21 | 33 |
| P8R | 1 | Head | – | 7 (10.4) | 27 | 3 | AD, SP | 1 | 1–3 | – | 23–41 | 30–49 |
| T21Afs*83 | 1 | Head | – | 1 (1.5) | – | 1 | – | – | – | – | – | – |
| P22R | 1 | Head | – | 1 (1.5) | 5 | – | AD | – | 1–2 | 1 | 22–29 | 24–25 |
| P22S | 1 | Head | – | 7 (10.4) | 71 | 1 | AD | – | 1–5 | – | 21–54 | 22–59 |
| P22T | 1 | Head | – | 2 (3) | 5 | – | AD | – | 2–3 | – | 21–36 | 33–39 |
| E90K | 1 | Head | – | 2 (3) | – | 2 | SP | 2 | 1 | 2 | 17–27 | 28 |
| L94P | 1 | Rod | Coil 1A | 1 (1.5) | 10 | – | AD | – | 1–2 | – | 35–38 | 29–40 |
| N98S | 1 | Rod | Coil 1A | 10 (14.9) | 4 | 8 | AD, SP | 4 | 1–2 | 11 | 18–35§ | 23–33§ |
| N98T | 1 | Rod | Coil 1A | 1 (1.5) | – | 1 | – | – | 1 | 1 | 44 | – |
| E140* | 1 | Rod | Coil 1B | 1 (1.5) | 2 | – | AR | – | 1 | – | 14 | – |
| A149V | 1 | Rod | Coil 1B | 1 (1.5) | – | 1 | – | – | 4 | – | – | – |
| E186* | 1 | Rod | Coil 1B | – | – | – | – | – | – | – | – | – |
| E210* | 1 | Rod | Coil 1B | 1 (1.5) | 4 | – | AR | – | 1 | 4 | 12–25 | 14–23 |
| Y265C | 1 | Rod | Coil 2A | 1 (1.5) | 7 | – | AD | – | – | – | – | – |
| L268R | 1 | Rod | Coil 2A | 1 (1.5) | 8 | – | AD | – | – | – | – | – |
| L268P | 1 | Rod | Coil 2A | 2 (3) | 17 | – | AD | – | 1–5 | – | 38–55 | 35–56 |
| L311P | 1 | Rod | Coil 2B | 1 (1.5) | 3 | – | – | – | 6 | – | 45–55 | 43–48 |
| C322_N326del | 1 | Rod | Coil 2B | 1 (1.5) | 11 | – | AD | – | 1 | – | 39–46 | 37–43 |
| Q332P | 1 | Rod | Coil 2B | 3 (4.5) | 21 | 1 | AD | – | 2–3 | – | 38–52 | – |
| L333P | 1 | Rod | Coil 2B | 1 (1.5) | – | 1 | – | – | – | – | – | – |
| Q334P | 1 | Rod | Coil 2B | – | – | – | – | – | – | – | – | – |
| L336P | 1 | Rod | Coil 2B | 1 (1.5) | – | 1 | – | – | – | – | – | – |
| I384F | 2 | Rod | Coil 2B | 1 (1.5) | 22 | – | AD | – | 1–4 | – | 34–46 | 32–46 |
| Y389C | 2 | Rod | Coil 2B | 1 (1.5) | 9 | – | AD | – | 6 | – | 48–49 | 50–52 |
| E396K | 3 | Rod | Coil 2B | 13 (19.4) | 63 | 3 | AD | – | 1–6 | 5 | 29–63 | 25–58 |
| R421* | 3 | Tail | Subdomain A | – | – | – | – | – | – | – | – | – |
| F439I | 3 | Tail | Subdomain A | 1 (1.5) | – | 1 | – | – | 3 | – | 45 | – |
| P440L | 3 | Tail | Subdomain A | 2 (3) | 3 | 1 | AD | – | 3 | – | – | – |
| Total/range | – | – | – | 67 (100) | 293 | 27 | – | 8 | 1–6 | 25 | 12–63 | 14–59 |
Families or isolated cases with positive family history.
Based on cosegregation analysis.
Proximal nerve segments excluded.
AD, autosomal dominant; AOO, age of disease onset; AR, autosomal recessive; MNCV, motor nerve conduction velocities; SP, sporadic.
For two mutations (E186* and Q334P), there was no clinical data available.40 43 R421* has been reported in a family with an overlapping myopathic–neurogenic phenotype39 and also in association with CMT40 but no clinical details were available for the latter.
Of the remainder 27 mutations, 17 were private to a single kindred and 10 were observed in two or more kindreds. Twenty-four mutations were clustered in six regions of the NFL polypeptide (figure 4): the initial segment of the head domain (amino acid positions 8–22), the junction between the head and the rod domains (90–98), coil 2A (265–268), the mid portion of coil 2B (311–336), the end portion of coil 2B (384–396) and the tail subdomain A (421–440). Mutations in the head domain and the two ends of the rod domain accounted for 75% of kindreds and four common mutations within these regions (P8R, P22S, N98S and E396K) were observed in 55% of kindreds. Only three mutations (E140*, A149V and E210*) were located in coil 1B. No mutations were observed in linker regions of the rod domain or the tail subdomain B.