Hereditary Spastic Paraplegia Type 5: Neurological, Bone & Vitamin D

Hereditary Spastic Paraplegia Type 5 (HSP5) is a rare genetic disorder that affects movement and muscle control. It belongs to a larger group of hereditary spastic paraplegias, characterized by progressive weakness and stiffness in the lower limbs. While primarily neurological, HSP5 also impacts bone health and metabolism, making early recognition crucial.

Understanding how HSP5 affects both the nervous system and skeletal structure can help guide management strategies.

Underlying Gene Involvement

HSP5 is linked to mutations in the SPG11 gene, which encodes spatacsin, a protein involved in intracellular trafficking and lysosomal function. While SPG11 mutations are more commonly associated with complex hereditary spastic paraplegia, specific variants have been identified in individuals with HSP5, suggesting overlapping molecular mechanisms. Spatacsin plays a key role in maintaining corticospinal tract neurons, which control voluntary movement. Disruptions in this protein lead to progressive axonal degeneration, causing the motor impairments seen in HSP5.

Spatacsin is also involved in autophagy, the process of degrading damaged organelles and proteins. Loss-of-function mutations in SPG11 result in defective autophagic flux, leading to the accumulation of dysfunctional lysosomes in neurons. This impairment is particularly harmful to long axons, such as those in the corticospinal tract, which rely on efficient intracellular transport. The failure of these processes accelerates neurodegeneration, reinforcing the progressive nature of HSP5.

HSP5 follows an autosomal recessive inheritance pattern, meaning affected individuals inherit two mutated SPG11 copies, one from each parent. Carriers, who have only one defective allele, typically do not exhibit symptoms but can pass the mutation to offspring. Advances in whole-exome sequencing have improved the identification of pathogenic variants, aiding genetic counseling and risk assessment.

Neurological Characteristics

HSP5 primarily affects the corticospinal tract, the major neural pathway responsible for voluntary motor control. Individuals experience spasticity, characterized by increased muscle tone and exaggerated tendon reflexes, especially in the lower limbs. This heightened stiffness leads to gait disturbances, often presenting as a scissoring walk due to excessive adductor muscle activity. Over time, mobility declines, sometimes necessitating assistive devices like canes or wheelchairs.

Additionally, degeneration of long motor axons contributes to muscle weakness, making activities such as climbing stairs or standing from a seated position increasingly difficult. Unlike spasticity, which increases resistance to passive motion, weakness affects the ability to generate force. Electrophysiological studies indicate that while peripheral nerves remain largely unaffected, central motor pathways show progressive impairment, helping differentiate HSP5 from other neuromuscular disorders.

Cognitive involvement, though not as pronounced as in other SPG11-related conditions, has been observed in some individuals. Mild executive dysfunction, such as difficulties with planning and problem-solving, has been reported, likely due to spatacsin’s role in neuronal maintenance. Neuroimaging studies, particularly MRI, have revealed thinning of the corpus callosum in some cases, a structural change seen in other SPG11-related disorders. This may contribute to deficits in interhemispheric communication, though its impact on daily functioning remains under investigation.

Musculoskeletal Changes

Progressive motor dysfunction in HSP5 leads to significant changes in muscle structure and skeletal alignment. Chronic spasticity in the lower limbs causes muscle imbalances that reshape posture and movement patterns. Over time, this persistent tension contributes to joint contractures, particularly in the hips, knees, and ankles, further limiting flexibility and mobility. Many individuals develop an equinovarus foot posture, where the foot points downward and inward due to unopposed muscle activity, affecting walking mechanics and increasing the risk of falls.

Weight-bearing joints adapt to abnormal biomechanics, leading to skeletal deformities, particularly in the spine and pelvis. Scoliosis, a lateral curvature of the spine, is common due to uneven muscle forces acting on the vertebral column. Severity varies, with some cases requiring orthopedic intervention. Pelvic obliquity, where the pelvis tilts asymmetrically, further disrupts balance and movement. These skeletal changes, combined with muscle weakness, make maintaining an upright posture increasingly difficult, contributing to fatigue and discomfort.

Bone Health And Vitamin D

Bone density and mineralization are areas of concern in individuals with HSP5. Chronic muscle spasticity and reduced mobility lead to diminished mechanical loading on bones, a key factor in maintaining bone strength. Over time, limited weight-bearing activity decreases bone mineral density (BMD), raising fracture risk, particularly in the femur and pelvis. Studies on neurological disorders affecting mobility have consistently shown lower BMD scores, highlighting the need for proactive skeletal monitoring.

Vitamin D is essential for bone metabolism, facilitating calcium absorption and maintaining appropriate serum calcium and phosphate levels. Deficiency is common in individuals with limited mobility due to reduced sun exposure, a primary source of endogenous vitamin D synthesis. Dietary intake and gastrointestinal absorption issues may compound deficiencies, leading to secondary hyperparathyroidism, where elevated parathyroid hormone levels accelerate bone loss.

Diagnostic Methods

Diagnosing HSP5 requires clinical evaluation, neuroimaging, and genetic testing. Given symptom overlap with other hereditary spastic paraplegias and neurodegenerative disorders, a detailed assessment of motor function and disease progression is essential. Physicians evaluate spasticity, hyperreflexia, and gait abnormalities, often using standardized scales like the Spastic Paraplegia Rating Scale (SPRS) to quantify severity. A thorough family history aids diagnosis, particularly when multiple relatives exhibit similar symptoms.

Magnetic resonance imaging (MRI) helps distinguish HSP5 from other neurological conditions. Many individuals with SPG11 mutations exhibit corpus callosum thinning, a structural abnormality less common in pure hereditary spastic paraplegia. White matter abnormalities may also be present. However, since these findings are not exclusive to HSP5, genetic testing is necessary for confirmation. Whole-exome sequencing or targeted SPG11 gene analysis can identify pathogenic variants, enabling precise diagnosis and genetic counseling. Early identification facilitates symptom management and informs reproductive choices for affected families.