A review of the genetic spectrum of hereditary spastic paraplegias, inherited neuropathies and spinal muscular atrophies in Africans

Table 2 Genetic causal variants of Charcot-Marie-Tooth (CMT)-related disorders reported in African populations

Ref	Country	Disease	Inh	AAO, years	Phenotypic features in addition to CMT	Gene	Gene variant	Gene Variant Assessment
Ref	Country	Disease	Inh	AAO, years	Phenotypic features in addition to CMT	Gene	Gene variant	Proband count	Segregation	Pop Freq
North Africa
[24, 39,40,41]	Algeria^± Morocco⁺	CMT2B1	AR	2 – 27	± proximal LL weak; ± scoliosis; axonopathy	LMNA	R298C^a	28	Yes	Yes
[24, 42, 48, 49, 51]	Morocco⁺ Tunisia⁺ Morocco⁻	CMT4A	AR	< 2 1–6 3	± kyphosis; claw hands; ± proximal LL weak; demyelinating ± proximal LL weak; claw hands; axonopathy ± proximal LL weak; ± diaphragm; axonopathy	GDAP1	W31* P78L (S194^b) R161H S194 ^a,c(R310Q^b)	2 3 1 8	No Yes No Yes	No Yes Yes Yes
[37]	Algeria⁺	CMT4B1	AR	1 – 12	Chest deformity; claw hands; ± vocal cord paralysis; demyelinating	MTMR2	p.R111fs	1	Yes	Yes
[47]	Tunisia⁺/Morocco⁺	CMT4B2	AR	2 – 15	± Glaucoma; demyelinating	MTMR13	R1196^a Q956	1 1	Yes Yes	Yes Yes

Ref	Country	Disease	Inh	AAO	Phenotypic features in addition to CMT	Gene	Gene variant	Proband	Segr	P Freq
[50]	Algeria	CMT4C	AR	4–10	Scoliosis; ± cranial neuropathy (hypoacusia/facial); demyelinating	SH3TC2	E731fs (Het) c.1178-1G > A R904^a R954 ^a	1 1 1 1	No No Yes No	No No No No
[37]	Algeria⁺	CMT4F	AR	10–12	Kyphoscoliosis; ± sensory ataxia; demyelinating	PRX	p.Arg364Ter	1	Yes	Yes
[43,44,45,46]	Tunisia^+/ Algeria⁺	CMT4H	AR	< 2	Scoliosis; “Ataxia”; demyelinating	FGD4	A172fs M298T R442H	1 1 1	No Yes Yes	Yes Yes Yes
[52, 53]	Algeria⁻	dHMN	AD	11–35	UL motor axonopathy	GARS	G526R	4	Yes	No
Sub-Saharan Africa
[54]	Nigeria⁻	CMT1B	AD	> 50	Demyelinating	MPZ	S78W	1	No	Yes
[56]	Mali⁺	CMT2D	AR	12	UL motor/sensory; ± seizures; S/M axonopathy	GARS	S265Y (Het)	1	No	No
[55]	Ivory Coast⁺	CMTint	AR	< 10	Proximal weak; MRI-WM; raised CK; conduc. blocks	PLEKHG5	C35fs	1	Yes	Yes

AAO, Age of Onset (years); Inh, inheritance pattern; AD, Autosomal dominant; AR, Autosomal recessive; S, sporadic; cog, cognitive abnormalities; SM neuropathy refers to sensori-motor polyneuropathy; PNP, peripheral neuropathy unspecified; ‘axonopathy’ refers to electrophysiological studies showing axonal loss (either motor (M) or sensory (S)) or ‘demyelinating’ slowing of conduction velocities; conduc. blocks refers to conduction blocks at unusual sites on electrophysiological testing; UL, upper limb; LL, lower limb; CMTint. refers to intermediate CMT (or distal spinal muscular atrophy type 4/DSMA4); dHMN or distal hereditary motor neuropathy (also classified as DSMA5); MRI-WM white matter signal changes on brain MRI; ⁺, consanguinity; ⁻, no consanguinity; HGVS, Human Genome Variation Society protein (p.) level and splice-site coding (c.) level recommendations (version 20.05)
Gene Variant score: Proband count, number of probands per variant; Segregation – yes when the pathogenic variant segregation was shown within the family (see methods); Pop. freq., Population frequency- yes when there was an attempt at assessing controls in the same population
^aVariant has been reported in non-African probands/families
^bCompound heterozygous; GDAP1 S194* was reported as a compound heterozygous variant in two families with P78L and R310Q, respectively
^cPresent in gnomAD v2/v3 (see Additional file: table for frequencies)

ISSN: 1750-1172