Childhood onset hereditary spastic paraplegia

Gene: GJC2

I don't know

PMID: 19056803 Orthmann-Murphy et al., 2008
3 family members homozygous for GJC2 p.Ile33Met. Presentation: late-onset, slowly progressive, complicated spastic paraplegia, with normal or near-normal psychomotor development.
Individual III-5 walked at 20 months, and developed progressive spastic paraplegia and dysarthric speech beginning in her teens, becoming wheelchair bound at age 30. Mild cognitive impairment.
Individual III-11 - showed signs of mild motor difficulties since infancy, started to worsen in his 20s, walks with a cane at 36yo. Mild learning impairment.
Individual III-8 - history of slowly progressive walking difficulties in his 30s, walks without assistance

PMID: 22833003 Zittel et al., 2012
Patient with 'complicated hereditary spastic paraplegia'. 38yo patients, noticed mild motor difficulties in his 20s, as well as progressive gait disturbance and leg stiffness at age 29yo. Mild learning impairment. Sequencing of GJC2 revealed compound het variants: p.R101L on maternal allele, and p.F227C; p.H412Y both on paternal allele.

PMID: 31431325 Kuipers et al., 2019
2 siblings from a Turkish family carrying a homozygous GJC2 mutation (c.820G>C, p.Val274Leu), presenting with late-onset (30-40yo) ataxic and pyramidal disturbances, and parkinsonism in one of them. Brain MRI showed hyperintense signal in T2-weighted images consistent with hypomyelination.

PMID: 37915394 Ghasemi et al., 2023
Iranian family, proband with spastic paraplegia, age of onset at 13 years old. WES revealed a homozygous variant in GJC2: c.14G>T, p.Ser5Ile, which cosegregated in affected individuals. However, the proband's affected sisters were diagnosed with hypomyelinating leukodystrophy instead, with ages of onset 6 months & 2 years old. Common phenotype in all 3 patients: lower limb spasticity, hyperreflexia, pyramidal tract syndrome, dystonia, ataxia, and urinary problems. Heterozygous carriers in the family were unaffected.

GJC2 is putatively linked to Spastic paraplegia 44, autosomal recessive, OMIM:613206 (OMIM accessed 12th Jan 2026).

Created: 12 Jan 2026, 3:53 p.m. | Last Modified: 12 Jan 2026, 3:53 p.m.

Panel Version: 8.24

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Spastic paraplegia 44, autosomal recessive , OMIM:613206

Publications

• 19056803
• 22833003
• 31431325
• 37915394

Red List (low evidence)

Single family with adult onset reported. Additional very late onset biallelic patient identified using Sheffield panel.

Created: 9 May 2019, 5:28 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 19056803

Variants in this GENE are reported as part of current diagnostic practice

I don't know

Red gene with Green GLH rating, Gene discussed in view of discrepant rating(s) from GLH(s). Amber rating agreed at the GMS Neurology Specialist Test Group Webex on 17th May 2019.

Created: 21 May 2019, 4:50 p.m.

Rating and review submitted on behalf of James Polke (Neurogenetics Laboratory,Institute of Neurology, London), on behalf of London North GLH for GMS Neurology specialist test group.

Created: 9 May 2019, 4:54 p.m.

Red rating on Hereditary spastic paraplegia panel 1.198

Lots of accounts linking this gene with "Pelizaeus-Merzbacher-like" disorder. Needs more expert curation in case PLP is a ddx for HSP, but given that PLP1 isnt in HSP panel this looks unlikely
Chris Buxton (North Bristol NHS Trust), 27 Nov 2018. Amber rating submitted.

This gene is on the Hereditary Spastic Paraplagia (HSP) NGS Panel in the UCLH National Hospital for Neurology and Neurosurgery & Institute of Neurology (NHNN) Neurogenetics genetic testing manual: "GJC2 encodes a gap junction protein which plays a key role in central myelination and is involved in peripheral myelination in humans. Mutations in this gene have been associated with autosomal recessive Pelizaeus-Merzbacher-like disease-1 (SPG44)." It is a confirmed DD gene for spastic paraplegia 44, with monoallelic inheritance (OMIM states recessive inheritance).
Ellen McDonagh (Genomics England Curator), 14 Jun 2016

Only a single family described with this phenotype, many more cases with the above phenotypes
emma baple (Genomics England Curator), 7 Feb 2016 Red rating submitted

Created: 2 May 2019, 4:01 p.m.

Green List (high evidence)

reported in several unrealted families with LEUKODYSTROPHY, HYPOMYELINATING, 2 and clincial feature of spasticity, 3 affected members of an Italian family with spastic paraplegia-44 ,multiple affected members of a large 3-generation family with autosomal dominant hereditary lymphedema. In sheffield HSP panel

Created: 28 Apr 2019, 4:16 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Leukodystrophy, hypomyelinating,2, 608804, AR; Spastic paraplegia 44, autosomal recessive, 613206, AR; Lymphatic malformation 3, 613480, AD