Spinal Muscular Atrophy (SMA)

SMA presents a broad phenotypic spectrum with classification based on the age of onset:

SMA Type 0 (Prenatal Form)

• Onset: Prenatal (reduced fetal movements).

• Manifestations: Severe hypotonia, immediate respiratory failure.

• Prognosis: Death (exitus) within the first days or weeks of life.

• Genetics: Homozygous SMN1 deletion, 1 copy of SMN2.

SMA Type 1 (Infantile Form; Werdnig-Hoffmann Disease)

• Onset: Within the first 6 months of life.

• Characteristic Signs: Frog-leg posture, tongue fasciculations.

• Manifestations: Severe hypotonia (“floppy baby syndrome”) from birth; never achieving the ability to sit without support; early respiratory failure (often the determining factor for prognosis); dysphagia (feeding difficulties, risk of aspiration).

• Prognosis: Life expectancy of less than 2 years in the absence of therapeutic interventions.

SMA Type 2 (Intermediate Form)

• Onset: Between 7 and 18 months of life.

• Manifestations: Ability to sit is achieved, but independent walking is impossible. Slow and progressive loss of acquired functions. Respiratory failure and dysphagia are often present.

• Complications: Frequent/progressive scoliosis, recurrent respiratory infections, dysphagia.

Il “Centro Dino Ferrari”, in synergy with the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, offers comprehensive management for patients with Spinal Muscular Atrophy (SMA), covering everything from clinical and molecular diagnosis to the administration of all currently available therapies.

Clinical Suspicion & Red Flags

Diagnosis often begins with the identification of key clinical signs:

• Neonatal Hypotonia: Known as “floppy baby syndrome.”

• Motor Delay: Failure to reach or loss of established motor milestones.

• Proximal Weakness: Symmetrical weakness greater in the legs than the arms.

• Tongue Fasciculations: Small, involuntary muscle twitches on the tongue.

• Family History: Consistent with an autosomal recessive inheritance pattern.

Genetic Diagnostics (First-Line Testing)

The gold standard for diagnosis is molecular analysis, which confirms over 95% of cases:

• Primary Methods: MLPA (Multiplex Ligation-dependent Probe Amplification) or quantitative PCR to detect SMN1 deletions and determine the SMN2 copy number.

• Negative Results: If SMN1 deletion is not found but clinical suspicion remains, direct or Next-Generation Sequencing (NGS) of the SMN1 gene is performed.

• Research & Advanced Analysis: The Center is equipped for qualitative/quantitative analysis of SMN1/SMN2 transcripts and SMN protein levels.

Early Detection and Prevention

• Newborn Screening: Now implemented in Italy, it identifies SMN1 deletions at birth, allowing for pre-symptomatic treatment and significantly better clinical outcomes.

• Prenatal Diagnosis: Available for at-risk families via amniocentesis or chorionic villus sampling (CVS) to facilitate appropriate genetic counseling.

Functional and Multidisciplinary Evaluation

Once diagnosed, patients undergo rigorous monitoring using standardized tools:

• Motor Scales: Specific scales such as CHOP INTEND (for infants), HFMSE, and RULM (for older/adult patients).

• Respiratory Monitoring: Spirometry, respiratory pressure tests (MIP/MEP/SNIP), and polysomnography (sleep study).

• Bulbar Assessment: Evaluation of swallowing via FEES or videofluoroscopy.

Genotype-Phenotype Correlation

The number of SMN2 backup copies serves as a primary predictor of disease severity:

• 1–2 copies: Generally associated with Type 1 (severe).

• 3 copies: Generally associated with Type 2 or 3.

• 4 or more copies: Generally associated with Type 3 or 4 (milder).

Diagnostic Strategy Flowchart

Clinical Suspicion → Genetic Testing (SMN1/SMN2) → Functional Assessments → Complication Screening → Genetic Counseling