Presentation and Progression

Heterogeneous Presentation
It is difficult to generalize LSD symptoms. Although the diseases share a common basic pathogenesis, the different types of substrate stored and locations of storage lead to tremendous clinical variability across the LSD category and often even within a single disease.[1, 2] Clinical manifestations tend to be progressive, as more waste substrate accumulates over time.

As a group, LSDs affect nearly every bodily system,[2] and symptoms can vary in severity from relatively mild somatic manifestations to severe and rapidly progressing neurologic pathologies. Many of the diseases are classified into separate sub-types based on factors such as age of onset, affected organs/systems, and severity. But even those without formal sub-types generally encompass a spectrum of clinical manifestations.^[3]

“Red Flag” Symptoms
While no single symptom is an LSD hallmark, several frequently present across enough of the disorders that they can be considered “red flags” to raise a physician’s suspicion and prompt further investigation. LSD symptoms often present in clusters, so the appearance of more than one of these is even more suggestive: ^{[1, 2, 3, 4]}

Coarse facial features	Corneal opacity
Angiokeratoma	Hepatosplenomegaly

Coarse facial features (sometimes with macroglossia)

Corneal clouding or related ocular abnormalities

Angiokeratoma

Umbilical/inguinal hernias

Short stature

Developmental delays

Joint or skeletal deformities

Organomegaly (especially liver and spleen)

Muscle weakness or lack of control (ataxia, seizures, etc.)

Neurologic failure/decline or loss of gained development

Particularly noteworthy are any signs of degenerative process--such as loss of motor skills, increasing dementia or behavioral abnormalities, and muscular or neurologic deterioration--that suggest a progressive disorder.^[2]

Progression and Outcome
The LSDs with neurologic involvement can often be the most severe, marked by rapid decline and high mortality rates.^[5] But generally, predicting LSD progression and outcome is challenging, especially in later-onset patients.^[1]

Often, a single disease is associated with several different gene mutations, which may partly account for the disease’s clinical heterogeneity. Nevertheless, genotype-phenotype correlations are not always consistent; the very same mutation may result in quite different outcomes in different patients.^[2] Other factors can also influence how a disease progresses:^[4] residual enzyme activity (versus complete deficiency); treatment or supportive care (and when in the disease course it is initiated); environmental influences; and unknown genetic factors.

Early identification and diagnosis is essential. Early intervention is especially important for the most serious and debilitating symptoms--particularly neurologic and skeletal--which once established often do not respond to even disease-specific therapies.^[1] (For more information on LSD therapies and management, see the Disease Management page.)

References

1. Wenger, DA. Insights into the Diagnosis and Treatment of Lysosomal Storage Diseases. Arch Neurol; 60: 322-328.

2. Wilcox, WR. Lysosomal Storage Disorders: The Need for Better Pediatric Recognition and Comprehensive Care. Journal of Pediatrics; May 2004: S3-S14.

3. Meikle, PJ, et al. Prevalence of Lysosomal Storage Disorders. JAMA; 281: 249-254.

4. Muenzer, J. The Mucopolysaccharidoses: A Heterogeneous Group of Disorders with Variable Pediatric Presentations. Journal of Pediatrics; May 2004: S27-S34.

5. Desnick, RJ, Schuchman, EH. Enzyme Replacement and Enhancement Therapies: Lessons from Lysosomal Storage Disorders. Nature Reviews - Genetics. 2002; 3: 954-966.