Wide Phenotypic Spectrum of PNMHH Patients With p.R941L Mutation in MYH14.

Dear Editor,

The MYH14 (MIM 608568) gene encodes a member of the nonmuscle myosin heavy-chain II family that affects cytoskeletal actin and regulate cell motility, polarity, and mitochondrial function.1 Mutations in MYH14 have been reported to cause autosomal dominant nonsyndromic deafness 4A (DFNA4A; MIM 600652).23 Our research group first reported the MYH14 p.R941L mutation in a large autosomal dominant Korean family in 2011 (family ID: FC317).4 This new type of rare genetic disease was registered in the OMIM database (MIM 614369, https://www.omim.org/) with the abbreviated name of PNMHH to reflect its complex phenotypes of peripheral neuropathy (PN), myopathy, hearing loss (HL), and hoarseness (Ho). The p.R941L mutation has subsequently been reported in two families in the United States of America and Canada.56

In the present study, we identified a second Korean family (family ID: FC1126) with the same MYH14 p.R941L mutation (Supplementary Fig. 1 in the online-only Data Supplement). The affected individuals exhibited PN, HL, Ho, and myopathy, with phenotypes similar to those for the previously described Korean PNMHH family.4 Audiological studies showed bilateral sensorineural HL, with greater impairment at high frequencies (Supplementary Fig. 2 in the online-only Data Supplement). Hoarse voice was present in both affected individuals, but paresis of the vocal cords was not found. The affected individuals exhibited distal leg muscle atrophy. MRI showed abnormal fatty infiltration and muscle atrophy in the lower extremities similar to the findings in the previous Korean family, and sequential muscle involvement according to the disease duration was also observed (Supplementary Fig. 3 in the online-only Data Supplement).4 Fatty infiltration and atrophy were present in the anterior compartment of the legs in the early stage (Supplementary Fig. 3C in the online-only Data Supplement), while posterior-compartment leg muscles were affected in the late stage (Supplementary Fig. 3D in the online-only Data Supplement).

It is of considerable interest that a wide phenotypic spectrum was revealed by comparing the clinical features among the four PNMHH families (including the present family) (Table 1). As the main phenotypes, PN and HL were observed in all of the families, while myopathy and Ho were only observed in two Korean families. When the PN types were compared in detail, the American family was reported to have distal hereditary motor neuropathy without sensory disturbance,5 but the other three families exhibited sensory loss, which is consistent with hereditary motor and sensory neuropathy and axonal Charcot-Marie-Tooth disease type 2.46

Table 1

Clinical manifestations of PNMHH patients with the p.R941L mutation in MYH14

Patients		Korean 1 (FC1126)		Korean 2 (FC317)	American	Canadian
		III-2	II-2
No. of patients		1	1	15	11	4
Phenotype		CMT2, HL, Ho, myopathy	CMT2, HL, Ho, myopathy	CMT2, HL, Ho, myopathy	dHMN, HL	CMT2, HL
Age at examination (yr)		25	55	11–52	26–77	23–58
Age at onset (yr)
	Muscle weakness	10	8	5–14	4–23	9–10
	HL	23	14	15–40	4–67	0–4
Muscle power (MRC scale)*
	Shoulder abduction	5	5	3 to 5	3- to 5	5
	Elbow flexion	5	5	4 to 5	4- to 5	5
	Elbow extension	5	5	4+ to 5	4 to 5	4- to 5
	Wrist extension	5	4+	4+ to 5	4 to 5	4- to 5
	Wrist flexion	4+	4+	4- to 5	4- to 5	4- to 5
	Finger extension	4	4	4- to 5	ND	3 to 5
	Finger flexion	4–	4	2 to 5	ND	3 to 5
	Finger abduction	3	3	2 to 5	4- to 4+	3 to 5-
	Hip flexion	4+	4	0 to 5	2 to 5	5
	Knee extension	4+	4+	0 to 5	3– to 5	5
	Knee flexion	4	4	4- to 5	3– to 5	5
	Ankle plantarflexion	5	4	3 to 5	3 to 5	3 to 5-
	Ankle dorsiflexion	0	0	0 to 5	2 to 5	1 to 4
Sensory disturbance		Yes	Yes	Yes	No	Yes
Ankle jerk reflex†		A	A	N to A	N to A	D to A
Foot deformity		Yes	Yes	Yes	Yes	Yes
Creatine kinase (IU/L)‡		290	213	63–548	ND	ND
Echocardiography		Constrictive pericarditis	Atrial flutter	Normal	ND	Normal
Lower limb MRI		Anterior calf muscle involvement	Whole calf muscle involvement	Sequential pattern of calf involvement	ND	Calf muscle fatty involvement
Electromyography		Neuropathy, myopathy	Neuropathy, myopathy	Neuropathy, myopathy	Neuropathy	Neuropathy, polyphasic motor units
Muscle biopsy		ND	ND	Size variation, grouping, inclusions§	ND	ND
Reference		This study	This study	4	5	6

*MRC scale: 0=no contraction; 1=trace of contraction; 2=active movement without gravity; 3=active movement against gravity; 4=active movement against gravity and resistance; 5=normal power; †Ankle jerk reflex: N=normal; D=diminished; A=absent; ‡Creatine kinase reference range: 0–170 IU/L; §Marked variation of muscle fiber size and grouping of muscle fiber types. Notably, the electron micrographs frequently revealed subsarcolemmal accumulation of enlarged mitochondria with variable-size rectangular or elongated rhomboidal paracrystalline inclusions in two affected individuals.

CMT2, Charcot-Marie-Tooth disease type 2; dHMN, distal hereditary motor neuropathy; HL, hearing loss; Ho, hoarseness; MRC scale, medical research council scale; ND, not done; PNMHH, peripheral neuropathy, myopathy, hearing loss, and hoarseness.

While HL was observed in all of the families, the onset age and severity varied between the families and even between individuals within a single family. Approximately half of the affected individuals showed no noticeable HL. HL in the Canadian patients occurred prelingually or with an early onset (age 0–4 years), but the other patients exhibited a broad range of HL onset ages, from preteens to the 60s (Supplementary Fig. 4A in the online-only Data Supplement). Muscle weakness was observed in all patients. The age range of muscle weakness onset was less broad (4–23 years) than that for HL (Supplementary Fig. 4B in the online-only Data Supplement). However, the severity and involved structures varied between the families. In most cases, HL occurred after muscle weakness except in the affected Canadian patients.

Muscle biopsies in two patients and electromyography yielded clear myopathic evidence in the Korean families. The patient exhibited a creatine kinase level of 548 IU/L, which is 3.2-fold higher than normal. However, myopathy was not diagnosed in the American and Canadian families who were examined using only electromyography (i.e., without muscle biopsies).

MYH14-mutant mice exhibit cardiac myopathy as well as HL,7 but none of the present affected individuals showed cardiomyopathy. Atrial flutter and constrictive pericarditis were observed in each patient of the second Korean family, but these conditions did not seem to be related to the MYH14 mutation.

Most mutations in MYH14 cause nonsyndromic HL, while only the p.R941L mutation exhibits various phenotypes corresponding to syndromic HL. Almutawa et al.6 suggested that the MYH14 p.R941L mutation functions in a dominant-negative fashion, inhibiting mitochondrial fission especially in the cell periphery. These reasons for the wide phenotypic spectrum of the PNMHH patients are still valid, but it may also be partly due to differences in race- or individual-specific genetic backgrounds, including genetic modifiers. It is recommended that mutational screening for MYH14 be performed when PN and HL with or without sensory disturbances occur together in a patient.