Familial Case Series of Neurodegenerative Disorders With Hematobiochemical Correlates: Insights From Four Related Patients

Technical Summary: Familial Case Series of Neurodegenerative Disorders With Hematobiochemical Correlates

Problem Statement
Inherited neurodegenerative disorders, specifically Spinocerebellar Ataxias (SCAs) and Hereditary Spastic Paraplegias (HSPs), exhibit significant intrafamilial phenotypic heterogeneity. This variability often complicates diagnosis, as a single genetic mutation can manifest as distinct clinical entities ranging from pure cerebellar ataxia to spastic paraplegia or peripheral neuropathy. Furthermore, the systemic nature of these diseases—particularly hematological and autonomic manifestations—is frequently under-recognized or dismissed as secondary complications rather than intrinsic disease features. This case series addresses the challenge of diagnosing familial neurodegeneration when phenotypes diverge within a single pedigree and seeks to characterize the systemic correlates, specifically hematobiochemical anomalies, associated with these conditions.

Methodology
The study presents a retrospective case series of four related patients from a single Indian pedigree, adhering to the CARE (CAse REport) guidelines. The cohort included:

• Case 1: A 54-year-old male (deceased at 57) presenting with sensory-motor peripheral neuropathy.
• Case 2: A 54-year-old female sibling of Case 1, presenting with an HSP phenotype.
• Case 3 (Index Proband): A 47-year-old female presenting with classic SCA3 features.
• Case 4: A 36-year-old male first cousin of the proband, presenting with sensory-motor peripheral neuropathy and early-onset symptoms.

Data collection involved comprehensive neurological examinations, structural neuroimaging (Brain CT and Abdominal Ultrasound), and detailed hematobiochemical profiling (Complete Blood Count, serum electrolytes, uric acid, and peripheral blood smear analysis). Molecular confirmation was performed via triplet repeat-primed polymerase chain reaction (PCR) targeting the ATXN3 gene on chromosome 14q32.1 for the index proband. Other repeat expansion disorders (SCA1, 2, 6, 7, 10, 12, and DRPLA) were screened and found negative in the proband.

Key Results

1. Phenotypic Variability: Despite sharing a familial lineage, the four patients presented with divergent clinical phenotypes. While the index proband (Case 3) exhibited the classic triad of cerebellar ataxia, dysarthria, and pyramidal signs, her relatives presented with HSP-like spasticity (Case 2) or predominant sensory-motor peripheral neuropathy (Cases 1 and 4).
2. Molecular Confirmation: The index proband was genetically confirmed to have Spinocerebellar Ataxia Type 3 (SCA3)/Machado-Joseph Disease (MJD) via the detection of a pathogenic CAG triplet repeat expansion in the ATXN3 gene.
3. Hematological Anomalies: A recurring pattern of hematological dysregulation was observed across the cohort:
   • Anemia: Cases 1 and 3 exhibited microcytic hypochromic anemia (Hb 8.7 g/dL and 8.2 g/dL, respectively), while Case 2 required intermittent packed RBC transfusions due to symptomatic anemia.
   • Leukocytosis: Three of the four patients (Cases 1, 3, and 4) demonstrated persistent neutrophilic leukocytosis (Total Leukocyte Counts ranging from 13,700 to 14,800 cells/µL) with relative lymphopenia, suggesting a chronic systemic inflammatory state.
4. Systemic and Autonomic Dysfunction: The study identified significant extra-neural involvement, including:
   • Autonomic Failure: Neurogenic urinary retention (Case 1) and early-onset achalasia cardia (Case 4), confirmed via barium swallow.
   • Structural Changes: Brain CT imaging across all patients revealed mild ventricular dilation and varying degrees of cerebral/cerebellar atrophy.
5. Anticipation: Case 4 presented with an onset age of 31, significantly earlier than the 45-year onset observed in the older generation (Cases 1, 2, and 3), illustrating the genetic principle of anticipation typical of trinucleotide repeat disorders.

Key Contributions

• Documentation of Intrafamilial Heterogeneity: The series provides empirical evidence that a single ATXN3 mutation can manifest as SCA3, HSP, or peripheral neuropathy within the same family, challenging rigid diagnostic boundaries.
• Identification of Systemic Biomarkers: The paper highlights specific hematobiochemical correlates (microcytic hypochromic anemia and neutrophilic leukocytosis) and autonomic dysmotility (achalasia, urinary retention) as intrinsic features of the disease process rather than incidental findings.
• Clinical Framework: It offers a comparative framework integrating clinical, hematological, and imaging data to illustrate the multisystemic nature of inherited tract degenerations.

Significance and Claims
The authors assert that this case series underscores the necessity of viewing inherited ataxias and spastic paraplegias as systemic, multi-organ diseases rather than isolated neurological defects. The presence of consistent hematological and autonomic abnormalities suggests that polyglutamine toxicity and chronic inflammatory states are central to the disease pathology.

The paper claims that recognizing these systemic correlates is vital for:

1. Refining Diagnostic Pathways: Preventing misclassification of patients with atypical phenotypes (e.g., mistaking SCA3 for pure HSP or neuropathy) by considering systemic markers like anemia and leukocytosis.
2. Optimizing Management: Shifting care from reactive neurology visits to proactive, multidisciplinary management involving neuro-urology, gastroenterology, and nutritional support to address the "invisible multi-organ burden."
3. Public Health Planning: Highlighting the need for genetic counseling and family-based surveillance, particularly given the principle of anticipation which may lead to earlier onset and increased disability in successive generations.

The authors conclude that integrated, multidisciplinary management is essential for these familial clusters, especially in the absence of widely available disease-modifying therapies, to preserve functional capacity and patient dignity.