autosomal recessive spastic paraplegia type 76

Autosomal recessive spastic paraplegia type 76 (SPG76) is a very rare inherited neurological condition that primarily affects the long nerve pathways controlling movement and balance. It is caused by pathogenic variants in the CAPN1 gene, which provides instructions for making the calpain-1 protein important for normal function of the cerebellum and spinal cord. Symptoms usually begin in late adolescence or adulthood and progress slowly, leading to stiffness and coordination problems that interfere with walking. Because the condition affects fewer than one in a million people worldwide, many clinicians may be unfamiliar with it, making an accurate molecular diagnosis essential for affected individuals and their families.

Severity and symptoms vary widely between individuals. Not all individuals experience all features, and the pace of progression can differ even among siblings. Neurological features: The hallmark signs are lower-limb spasticity, brisk reflexes, and a scissoring or stiff-legged gait. Cerebellar atrophy is consistently reported and contributes to ataxia, dysmetria, and gait imbalance. Many people develop extensor plantar responses (Babinski sign) and upper-limb hyperreflexia, and some notice slurred speech (dysarthria). Peripheral neuropathy, distal sensory loss, or muscle weakness may appear later, occasionally leading to loss of ambulation. Musculoskeletal features: Chronic muscle overactivity can produce foot deformities, most often high-arched feet (pes cavus), though flat-footed valgus positioning or ankle clonus also occur. Progressive muscle stiffness may lead to skeletal muscle atrophy in the legs and require orthopedic evaluation. Autonomic and other features: Episodes of urinary urgency or incontinence are reported in a minority of adults. Mild cognitive or intellectual changes have been described, but severe cognitive decline is uncommon. Early presentation often involves subtle balance problems or tripping on uneven ground, prompting neurological evaluation. Over time, spasticity and ataxia typically worsen, while supportive therapies can help preserve mobility and independence.

SPG76 results from inheriting two altered copies of the CAPN1 gene, one from each parent. CAPN1 encodes calpain-1, a calcium-dependent enzyme that helps regulate neuronal structure and signaling; loss of its normal activity disrupts pathways essential for coordinated movement. The condition is inherited in an autosomal recessive pattern, meaning that carrier parents—who usually have no symptoms—have a 25% chance with each pregnancy of having an affected child. Because this condition is more common when parents share a common ancestor, carrier testing may be particularly relevant for families with shared ancestry. Genetic counseling is recommended for relatives to clarify carrier status, discuss family planning options, and provide personalized recurrence information.

Currently, management focuses on supportive care and symptom management. Treatment is tailored to the individual and typically involves a multidisciplinary team that may include neurologists, physiatrists, physical and occupational therapists, speech-language pathologists, orthopedic surgeons, and urologists. Regular surveillance is an essential part of long-term care, helping to identify potential complications before they become serious. Standard approaches include physiotherapy and stretching programs to maintain flexibility, assistive devices such as ankle-foot orthoses or walkers to improve gait stability, and speech therapy for dysarthria. Oral or intrathecal medications that reduce muscle tone can lessen spasticity, while orthopedic interventions may address disabling foot deformities. Bladder symptoms are managed with behavioral strategies or medications tailored by a urology specialist. Genetic counseling should be integrated into care to support family planning decisions. Patients should discuss management options with their healthcare team to determine which therapies are appropriate for their specific situation.

SPG76 usually follows a slowly progressive course. Many individuals remain able to walk for years or decades after onset, although some may eventually require walking aids or wheelchairs, especially if ataxia and spasticity worsen. Cognitive decline, when present, is generally mild. Outcomes depend on many factors, including age at diagnosis, response to spasticity management, access to rehabilitative services, and fall prevention strategies. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with neurologists familiar with hereditary spastic paraplegia and with genetic counselors who can provide guidance and support.