Spastic paraplegia 2

Alternate names

SPG2; SPPX2

Definition

A rare, X-linked leukodystrophy characterized primarily by spastic gait and autonomic dysfunction. When additional central nervous system (CNS) signs, such as intellectual deficit, ataxia, or extrapyramidal signs, are present, the syndrome is referred to as complicated SPG.

Epidemiology

• The prevalence and incidence of SPG2 have not been reported, but as part of the Pelizaeus-Merzbacher spectrum, SPG2 roughly accounts for about 20 % of cases.
• There have been approximately 20 cases published on SPG2.
• SPG2 affects males but some female heterozygotes presenting in adulthood with a milder phenotype have also been reported.

Cause

• SPG2 is due to missense substitutions affecting the PLP1 gene.
• PLP1 encodes the proteolipid protein (PLP), the most abundant protein of the myelin sheath in the central nervous system, and its alternatively spliced isoform (DM20).
• SPG2 is allelic to Pelizaeus-Merzbacher disease that is also due to PLP1 mutations.

Inheritance

X-linked recessive inheritance

Transmission is X-linked recessive.

Signs and symptoms

• SPG2 spans a continuum of phenotypes that goes from pure to complicated SPG2.
• Pure SPG2 manifests as early as infancy or early childhood (<5 years) but may be delayed until early adulthood.
• It presents with weakness, hyperreflexia, Babinski sign and spastic gait due to spastic paraparesis.
• Autonomic dysfunction (spastic urinary bladder and possibly bowel, with increased urinary and fecal frequency and incontinence) is frequent.
• Patients are able to walk and their speech is normal.
• There is no CNS involvement and no cognitive decline.
• Complicated SPG2 shares the same features as SPG2 but also shows additional CNS involvement like nystagmus, and ataxia that present in the first years of life.
• Optic atrophy may be present.
• Patients can also show a mild intellectual deficit.

Diagnosis

• Diagnosis is based on clinical, electrophysiologic, and neuroradiological findings.
• White matter N-acetyl aspartate levels are reduced.
• Brain magnetic resonance imaging (MRI) reveals patchy or diffuse hypomyelination on T2-weighted images.
• Patients with pure SPG2 can have very subtle T2 hyperintensity.
• Other MR techniques, including MR spectroscopy and diffusion tensor imaging are useful in the diagnosis of the disease.
• Molecular genetic testing of PLP1 confirms the diagnosis.

Antenatal diagnosis Prenatal genetic testing is possible when a family's underlying PLP1 mutation has been identified.

Treatment

• A son born to a female carrier has a 50% risk of inheriting the mutation and developing the disease, while a daughter has a 50% risk of being a carrier.
• All daughters of an affected male will be carriers but none of his sons will be affected.
• Management is multidisciplinary and involves neurologists, physical therapists, and orthopedic doctors.
• Treatment may include antiepileptic drugs for seizures, and physical therapy with antispasticity drugs (baclofen, diazepam, tizanidine, botulinum toxin, dantrolene) for spasticity.
• Regular surveillance is necessary.

Prognosis

Pure SPG2 patients show a normal life expectancy. In complicated SPG2 cases, patients deteriorate neurologically leading to a shorter life expectancy (between the fourth and seventh decade) typically from aspiration pneumonia, pulmonary embolism and other complications of generalized weakness.

NIH genetic and rare disease info

• NIH info on Spastic paraplegia 2

Spastic paraplegia 2 is a rare disease.

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