246. Accepted

Nonketotic hyperglycinemia

Nonketotic hyperglycinemia (glycine encephalopathy)

Pregnant complain
"frequent, continuous, rhythmic jerking of the fetus in utero before birth"
reflecting seizures that begin prenatally

Pathophysiology
- Defect mitochondrial glycine cleavage (GLDC/AMT)→ ↑glycine & ↑NMDAr activity

Presentation
First days w/ lethargy + intractable szs + jerks + hiccups + hypotonia
EEG burst-suppression evolving to hypsarrhythmia

Investigation
- FH
- Check Gluc, Na, Ca, Mg, ABG, lactate
- cEEG
- CSF:plasma glycine ratio, add NH3, lactate, plasma AA, urine organic acids, acylcarnitine profile
- bMRI
> spectroscopy→ glycine peak
> corpus callosum agenesis
- genetic panel

Management
- If persistent szs, treat empiric→ pyridoxine ± pyridoxal-5-phosphate and folinic acid

Infantile spasms

Infantile spasms

Definition
IS is time diagnosis
- Btw 3 to 18 months, peak 6 months
- 50% remission by age 3yo, 90% by age of 5yo

Important
↑risk→ TSC1&2 and down syndrome

Differentials
<3mo→ Ohtahara vs Sandifer
Evaluation
Prompt EEG and treatment delay→ assoc w/ worsens neurodevelopmental outcomes

245. Accepted

244. Missense mutations in the SNCA gene: Molecular mechanisms and clinical implications

Article type: Literature Review
Article title: Missense mutations in the SNCA gene: Molecular mechanisms and clinical implications

Journal: Molecular and Cellular Neuroscience
Year: 2026
Authors: Pranaya Gade, Nishant Patel, Jamir Pitton Rissardo, Jorge Patino, Ana Letícia Fornari-Caprara, and Ian M. Walker

ABSTRACT
The SNCA gene on chromosome 4 encodes the alpha-synuclein (αSyn) protein, which plays a central role in the pathogenesis of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). While αSyn has established roles in synaptic vesicle dynamics and neuronal signaling, alterations in SNCA regulation and sequence contribute to protein misfolding, aggregation, and loss of function. Alterations in secondary and tertiary structure, as well as protein aggregation, affect biochemical interactions, ultimately leading to pathogenesis. This review outlines the molecular architecture of the SNCA gene, including regulatory regions, alternative splicing, and untranslated regions that influence αSyn expression and isoform diversity. Seven missense mutations of the SNCA gene are discussed in detail from the genomic level, extending to phenotypic presentations. These missense mutations have different effects on the aggregation kinetics and fibril formation. Specific genotype-phenotype correlations are evident, with mutations such as A30P and H50Q commonly resembling idiopathic PD, E46K strongly associated with DLB, and G51D, A53T, and A53E linked to atypical parkinsonism and MSA-like syndromes. Differences in age at onset, disease progression, cognitive involvement, and response to therapy further reflect mutation-specific effects and modifying influences of allelic dosage and epigenetic regulation. Collectively, these findings emphasize the importance of SNCA genetic variation in shaping disease phenotype and progression. Improving the understanding of SNCA genotype-phenotype relationships in future studies may facilitate earlier diagnosis, refine prognostic stratification, and support the development of targeted, disease-modifying therapies for synucleinopathies.

Keywords: synucleinopathy; neurodegeneration; protein aggregation; molecular mechanisms; pathogenic variants; structural modeling.

Full text available at:

DOI

Citation
Gade P, Patel N, Rissardo JP, Patino J, Fornari-Caprara AL, Walker IM. Missense mutations in the SNCA gene: Molecular mechanisms and clinical implications. Mol Cell Neurosci 2026;104116. doi:10.1016/j.mcn.2026.104116.
Figure 1. Genomic location of the SNCA gene on chromosome 4.
Figure 2. Genomic organization, regulatory elements, and major transcript isoforms of the SNCA gene. The SNCA transcript prior to alternative splicing consists of six exons separated by five introns and is flanked by 5’ and 3’ UTRs. Key regulatory elements, including the promoter region, CpG and non-CpG methylation sites, transcription factor binding sites, intronic epigenetic regulatory regions, and alternative polyadenylation of the 3’ UTR, are shown. Major transcript isoforms generated through alternative splicing (SNCA 140, SNCA 112, SNCA 126, SNCA 98) are also depicted.
Figure 3. Timeline of reported cases of SNCA missense mutation in chronological order. A timeline of SNCA missense mutation discovery and patient reports. The first mutation was discovered in 1997 and new mutations and cases were reported throughout the 20 years following the first discovery.
Figure 4. Structural features of αSyn protein. The alpha synuclein protein consists of a lysine-rich, amphipathic membranebinding N-terminus with residues 1 to 60, a central hydrophobic NAC region with residues 61 to 95, and a negatively charged C-terminus with residues 96-140. The heterozygous SNCA gene mutations, A53T, A30P, E46K, G51D, H50Q, A53E, and A53V, cluster within the N-terminus domain and the seven repeat KTKEGV sequences are located throughout the N-terminal region and NAC region (Blazekovic et al., 2021; Whittaker et al., 2017). Adapted from Whittaker et al. (2017). License: https://creativecommons.org/licenses/by/4.0/
Table 1. Clinical presentation of SNCA missense mutations.

CPEO

Chronic progressive external ophthalmoplegia (CPEO)

Clues
- Common adult presentations of mitochondrial disease

Clinical features
- Classic: ophthalmoparesis + ptosis
> Pupil sparing
- Possible: proximal limb myopathy + bulbar involvement + reduced respiratory muscle strength

Presentations
- Isolated CPEO vs CPEO-plus
> Isolated→ only eyes; with anything else is CPEO-plus
> Kearns-Sayre syndrome triad
(CPEO + pigmentary retinopathy + onset before 20yo)

Genetics
- Half of cases→ 4977-bp mtDNA deletion
- Other half is multiple deletions in mtDNA
> Common: POLG, TWNK (C10orf2), SLC25A4

Workup
- Labs: can ↑CK & ↑lactate
- EMG: myopathic changes
- Muscle biopsy→ ragged-red fibers & COX-negative fibers
- Cardiac eval→ ECG & TTE
> Cardiac conduction block→ KSS
- oMRI→ EOM atrophy

DDx
- Seronegative MG
- OPMD
- Congenital myasthenic syndromes
- Myotonic dystrophy

Ttx
- Supportive
- If ptosis→ surgery/ prisms
- CoQ10 and others, evidence is limited
- Avoid mitochondrial-toxic medications

General advice for mito myoapthies
1) Succinylcholine→ ↑HyperK adn rhabdo
2) Propofol→ ↑Propofol syndrome
3) Volatile anesthetics→ prefer sevo
4) Avoid LR→ impaired lactate metabolism 

Forensic Psych

Forensic Psych

Visual hallucinations
- VH→ Olfactory→ Tactile
> Low probability of being psychiatry (olfactory & tactile), usually malingering, rarely neurological
> Drugs of abuse withdrawal

Orthostatic hypotension

Orthostatic hypotension (OH)

Management

Meds
Midodrine
-2nd dose before 0600PM to avoid nocturnal supine HTN

Stroke - Mortality

Stroke - Mortality

< 24h→ stroke severity
>24h→ quality hospital metric

Stroke - DVT prophylaxis

Stroke - DVT prophylaxis

Current ICH
- If rCTH (6h) is stable, theoretically okay to start DVT prophylaxis
*Guidelines say rCTH in 24, if stable okay to restart DVT prophylaxis

If starting full AC in-hospital
-There is no need for DVT prophylaxis
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