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Dewsbury et al. J Transl Genet Genom 2024;8:85-101 https://dx.doi.org/10.20517/jtgg.2023.58 Page 93

GM2 gangliosidosis Progressive neurological regression, seizures, Dysregulated ER calcium homeostasis [58]
(Tay Sachs) spasticity, deceleration in movement, ataxia, Neuroinflammation; the production of inflammatory mediators, cytokines and chemokines, Ccl2, Ccl3, Ccl4, Cxcl10, Cxcl13. [92]
tremors; Ccl2 displays chemotactic activity for monocytes, lymphocytes, and neutrophils. Ccl3 influences monocyte, lymphocyte, and [93]
psychosis neutrophil migration together with Ccl2, and activation of T cells and macrophages with Ccl4. Cxcl10 produced by
astrocytes recruits activated T lymphocytes by increasing their migration to the site of tissue damage in the cortex and
cerebellum. This leads to cytoplasmic vacuolation of nerve cells, deterioration of Purkinje cells, and neuronal death,
preceded by activated microglia expansion, macrophage and astrocyte activation (mouse model)

Mucolipidosis IV Mental impairment, speech impairment, Lack of the endolysosomal ion channel mucolipin1/ TRPML1/MCOLN1, with evidence of lysosomal accumulation of [94]
2+
spasticity, neuroaxonal dystrophy, blindness; gangliosides and heavy metals such as zinc and iron; Ca abnormalities; secondary mitochondrial dysfunction [7,95]
intellectual disability Changes in cytokine release (IFN-α1, IP-10) in response to TRPML1 loss of function and upregulation of interferon-gamma [96]
signaling results in defective brain myelination, oligodendrocyte dysfunction and pro-inflammatory activation of microglia [97]
and astrocytes [98]
Significant delays in expression of mature oligodendrocyte markers Mag, Mbp, and Mobp in the cortex early in life result in
hypomyelination and diminished oligodendrocyte maturation between the cortex/forebrain and cerebellum (mouse model)
2+
Mitochondria-lysosome contacts facilitate the direct transfer of Ca from lysosomes into the mitochondria, mediated by
TRPML1 which is disrupted in IV
Fabry disease Progressive motor and nonmotor Disrupt the autophagy-lysosomal pathway, leading to autophagosomal accumulation of phosphorylated a-synuclein in the [7,99]
2+
neurodegeneration; it remains unclear whether mouse brain TRPML1-mediated Ca -release is compromised [57]
these are associated with Parkinsonian
neurodegeneration
2+
Neuronal ceroid Dementia, motor disturbances, epilepsy, loss of Neuroinflammation. Mitochondrial dysfunction. Reduced ATP levels. Deficient mitochondrial Ca buffering. Mitochondrial [100]
lipofuscinoses vision, and early death. vacuolation [101]
Cognitive decline and seizures. Cysteine string protein alpha (CSPα) mislocalizes as aggregates to the neuronal soma instead of being targeted to the [102]
presynapse. This results in the decreased interaction between CSPα and SNAP-25, causing increased SNAP-25 degradation [103]
and impaired synaptic SNARE-complex assembly [104]
Failed autophagy results in accumulation of impaired neuronal mitochondria; mROS accumulation is observed in Cln7 [105]
neurons that mediate glycolytic enzyme PFKFB3 activation (mouse model) [106]
CLN8 deficiency decreases the complexity and size of the somatodendritic compartment, leading to neurodegeneration (rat [107]
model) [108]
CLN5 is a substrate of CRL3-KCTD7 E3s. In NCL, KCTD7 mutations result in the disruption of the interaction between
KCTD7-CUL3 or KCTD7-CLN5, leading to excessive CLN5 accumulation in the endoplasmic reticulum. CLN5 accumulation
disrupts the CLN6-CLN8 interaction and lysosomal enzymes, which causes the impaired trafficking of ER-to-Golgi lysosomal
enzymes. The C128Y mutation causes abnormal palmitoylation of CSPα and aggregates formation, also triggering lipofuscin
deposits in adult-onset NCL (human)
Pompe disease Limb–girdle muscle weakness. Mitochondrial calcium excess, increased ROS generation, decreased mitochondrial membrane potential, and decreased [7]
Intellectual disability, impaired visuospatial oxygen consumption and ATP production [109]
functioning. [110]

treatment, as well as improved overall cognitive function, compared to patients who had not received HSCT therapy . Patients who received HSCT also
[117]
showed no further decline in their IQ compared to untreated individuals. HSCT has also been shown to improve intellectual function in four patients with
AM, as well as improving their adaptive skills and verbal memory function in all patients . All four patients also demonstrated improved speech and hearing,
[118]
with no new skeletal abnormalities reported. A normalization in leukocyte alpha-mannosidase enzymatic activity was also observed in all four patients post-

HSCT. HSCT has more recently been shown to improve the clinical symptoms in patients with AM, mainly with intermediate or severe disease and symptoms