Hereditary Motor and Sensory Neuropathy Associated With Juvenile Glaucoma

Hereditary motor and sensory neuropathy (HMSN) belongs to a heterogeneous group of hereditary neurological disorders characterized by progressive muscular atrophy and weakness of limbs due to peripheral neuropathies or Charcot-Marie-Tooth disease (CMT), also known as peroneal muscular atrophy. Only a few cases were reported of an association of HMSN with primary optic atrophy or retinitis pigmentosa.^{1 - 6} We report on the cases of 3 sibs, the offspring of consanguineous Japanese parents, who had juvenile glaucoma or ocular hypertension in association with autosomal recessive HMSN. Two of the sibs had juvenile glaucoma and 1 had ocular hypertension. To our knowledge, the association of these neurological and ocular disorders has not previously been reported. The family may represent a new variant of heterogeneous HMSN.

Distinct neurological disease and glaucoma were found in a Japanese family who were residents in Amami-Ohshima, an island about 200 miles south from the mainland of Japan. As shown in Figure 1, 3 of 7 sibs were affected with both progressive peripheral neuropathy and primary glaucoma. Their parents were second cousins and showed no remarkable findings on neurological and ocular examination except for mild senile cataract. In 4 other sibs no abnormality was found on systemic and ocular examination.

The male proband, born in 1947, had no problems in physical or mental development in early childhood. At the age of 8 years, he was referred to our institution for investigation of complaints of blurred vision and seeing halos around light. He was diagnosed as having glaucoma and underwent filtering operations in 1955 at our institution. Subsequently, the patient received long-term follow-up by a local ophthalmologist, but he suffered a gradual progressive loss in vision. He returned to our institution at the age of 51 years and he showed advanced glaucoma in both eyes. Corrected visual acuity was 0.6 OD and 0.02 OS. Visual field test results revealed marked loss in the peripheral fields with remnants of about 10° in the central field. Applanation tonometries measured 19 mm Hg OD and 18 mm Hg OS. Functioning filtering blebs were present in the superior limbus of both eyes. The corneas were clear. Anterior chambers were normally deep and clear. Pupils were irregular owing to artificial iridectomy. Anterior chamber angles were open except for partial peripheral anterior synechiae due to glaucoma surgery. Trabecular meshwork had a normal appearance and width. The high iris insertion and hyperpigmentation of trabacular meshwork were not present in both angles. Some iris processes were seen but not prominent. With the exception of the artificial iridectomy, no iris abnormalities were observed. Lenses and vitreous cavities were clear. Both optic discs were pale with a cup-disc ratio of 100% and almost total loss of rim (Figure 2A).

This patient first had weakness of the lower limbs when he was approximately age 13. Since then, he suffered progressive impairment of gait and muscular atrophy and weakness that affected his lower limbs. Results from physical examination at age 51revealed a mentally healthy man with steppage gait with drop foot. Findings from neurological studies showed absence of deep tendon reflexes and sensory impairment of glove-and-stocking–like distribution in the limbs. Atrophy of the leg and thigh muscles was so marked that the lower limbs resembled an inverted champagne bottle (Figure 3A). The conduction velocities of peripheral motor nerves were severely diminished; the conduction velocity of median motor nerves was 21 m/s (control, 56 ± 4 m/s [mean ± SD]), and that of ulnar motor nerves was 19 m/s (control, 44 ± 4 m/s [mean ± SD]). The evoked response of the peroneal motor nerve was absent. Sensory nerve action potentials were almost absent. Findings of other physical studies were unremarkable. These findings were compatible with peripheral motor and sensory neuropathy.

A sister of the proband, born in 1950, had been visually asymptomatic during early childhood. At age 10 years, she was diagnosed as having bilateral glaucoma and underwent filtering surgery. At age 17, she had a complete loss of vision in her left eye. On examination at age 45, the corrected visual acuity was 0.2 OD and she was completely blind in the left eye. The left eye was soft and tended to become phthisic. In the right eye, corrected visual acuity was 0.3 and the visual field had only a small central island of vision. Applanation tonometry measured 30 mm Hg. The cornea was clear and measured 12 mm in diameter. There was a scarred bleb in the superior limbus with an irregularly shaped pupil because of the previous surgical iridectomy. The anterior chamber was normally deep and clear and the angle was open except for partial peripheral synechiae in the upper portion. The high iris insertion and hyperpigmentation of trabecular meshwork were not present in the angles of the right eye. Some iris processes were seen but were not prominent. The lens and vitreous were clear. Ophthalmoscopic examination revealed a pale optic disc with a cup-disc ratio of 100% (Figure 2B). The follow-up course of action for this patient was to prescribe antiglaucoma medications.

Physically, this patient claimed that she had been clumsy in running during the earlier years of her childhood because of a weakness of the limb muscles. Since about age 13 she suffered progressive muscular atrophy and weakness in her lower limbs. Physical examination findings at age 45 showed that she could walk unguided with steppage gait and with a high-arched, deformed foot. Muscular weakness and atrophy were more remarkable in the lower limbs. Nerve conduction studies revealed abnormalities similar to those in case 1: median motor nerve conduction velocity of 19 m/s (control 56 ± 4 m/s [mean ± SD]); ulnar motor nerve conduction velocity of 18 m/s (control, 44 ± 4 m/s [mean ± SD]). The activities of the peroneal motor and sural nerves were not recorded.

A younger brother of the proband, born in 1963, had long been asymptomatic visually. At age 26 years, he was noted to have an elevated intraocular pressure and the follow-up course of action taken was to prescribe hypotensive medications. He was referred to us at age 34 for assessment of ocular conditions. Corrected visual acuity and visual field were normal in both eyes. Intraocular pressure was 21 mm Hg OU. Corneas, irides, lenses, and vitreous cavities were unremarkable. The anterior chamber was normally deep and clear and the angle was open. A few iris processes were present. The ophthalmoscopic examination revealed mild temporal pallor and a cup-disc ratio of 50% in both optic discs (Figure 2C).

This patient had first noted muscular atrophy and weakness in his lower limbs at age 6. Results of physical and neurological examinations at age 34 revealed abnormalities similar to those in the affected brother and sister (Figure 3 B). Nerve conduction studies showed results similar to those in case 1: median motor nerve activity, not evoked; ulnar motor nerve conduction velocity of 18 m/s (control, 44 ± 4 m/s [mean ± SD]); and no evoked peroneal motor nerve and sural nerve activity.

Biopsies of sural nerve were done in each case. The nerve specimens were fixed overnight in 3% glutaraldehyde in 0.125M cacodylate buffer (pH, 7.4), washed, osmicated, and embedded in epoxy resin (Epon). Sural nerve pathologic findings for the 3 cases showed similar results. Light microscopic examination demonstrated severe loss of nerve fibers and abnormal myelin folding complexes (Figure 4A). Electron microscopic examination revealed that several myelinated fibers have an irregularly folded or extremely thickened myelin sheath (Figure 4B).

Molecular mutation analyses were performed for myocilin and CYP1B1 (GLC3A), known as causative for some cases of congenital or juvenile glaucoma using peripheral blood DNA. The results were negative in the 3 patients and their parents.

This family showed an association of juvenile-onset, progressive peripheral neuropathy and primary open-angle glaucoma. The ocular disease was featured by intraocular pressure elevation beginning in the first decade of life and progressive visual loss despite medical and surgical managements, which conforms to juvenile rather than congenital glaucoma. Two of the 3 sibs had advanced glaucoma in adolescence, and the remaining 1 had the preclinical stage of glaucoma or ocular hypertension.

Congenital or juvenile glaucoma rarely occurs in association with hereditary neurodegenerative disorders, including spastic paresis, Friedreich ataxia, and Ackerman syndrome.^{7 - 9} The neurological features of the patients in this family are (1) early-onset sensory and motor neuropathy, (2) severely damaged peripheral nerve conduction velocity, (3) histopathological changes in the sural nerve, and (4) autosomal recessive inheritance with parental consanguinity. The characteristic neurological disorder in this family is compatible with HMSN, a neurogenic syndrome encompassing 7 types with a heterogeneous group of hereditary peripheral neuropathies.¹⁰ Our family belongs to type IV HMSN, featured by autosomal recessive inheritance. Types VI and VII HMSN are characterized by associated ocular disorders. We found a few cases of type VI disorder in the literature. Schneider and Abeles¹ described 2 middle-aged brothers whose vision deteriorated in the first decade of life because of progressive optic atrophy. Hoyt² described a 17-year-old boy who developed acute bilateral visual loss due to optic nerve disease resembling Leber hereditary optic neuropathy. Barreira et al³ described 2 sibs with optic atrophy. With regard to type VII HMSN, Massion-Verniory et al⁵ described 2 sibs with retinitis and Khoubesserian et al⁶ described a woman aged 40 years with retinitis pigmentosa. Thus, previously reported cases of types VI and VII HMSN are seen with either primary optic atrophy or retinitis pigmentosa. To our knowledge, there is only 1 family described in the literature that has an association between HMSN and glaucoma; Arruda et al¹¹ reported on 3 cases in a family of Turkish origin developing HMSN and congenital glaucoma during the first decade of life.

As designated from clinical features, HMSN is also called CMT.¹² Autosomal recessive HMSN belongs to type IV HMSN or CMT4. Based on electrophysiological and histopathological abnormalities of peripheral nerves, CMT4 is subdivided into 3 types¹² : CMT4A, characterized by slow motor nerve conduction velocity and hypomyelination; CMT4B, by slow motor nerve conduction velocity and focally folded myelin sheath; and CMT4C, by normal motor nerve conduction velocity and absence of myelin change. Our patients had a reduction in the motor nerve conduction velocity and myelin disorganization such as irregular redundant loops and foldings. Together with the probable inheritance pattern, our patients are compatible with type IV HMSN or CMT4B. An association of type IV HMSN or CMT4B with early-onset glaucoma in our family and the family of Arruda et al ¹¹ may represent either a new clinical type of HMSN IV (CMT4B) or its variant.

A genetic analysis to define the association between neurological disorder and primary open-angle glaucoma is essential to elucidate its underlying pathogenesis. The gene responsible for CMT4A and CMT4B has been mapped in the 5q23-33, 8q13-21.1, and 11q23.^{13 - 15} We reported that the DNA haplotype in this family had no linkage to 5q or 8q, although not excluding a possibility of linkage to 11q23, and that further analyses failed to show any linkage to candidate genes such as myelin protein zero, peripheral myelin protein-22, connexin-32, or early growth response 2.¹⁶ The CMT1A duplication, the most common molecular abnormality of CMT, was not present in this family. With regard to glaucoma, findings from mutation analyses of myocilin or CYP1B1, known as pathogenic for some cases of congenital or juvenile glaucoma, were normal. Thus, the molecular genetic basis of this rare familial disease remains to be elucidated.

Corresponding author: Kazuhiko Unoki, MD, PhD, Department of Ophthalmology, Kagoshima University Faculty of Medicine, 8-35-1 Sakuragaoka, Kagoshima-shi 890-8520, Japan (e-mail: kazuhiko@m2.kufm.kagoshima-u.ac.jp).