D-Cycloserine for Serine Palmitoyltransferase Inhibition

At each visit a medication reconciliation will be performed which will include medications, vitamins, herbal preparations, and supplements. For each medication the investigators will record start and end dates of administration, dosage, frequency, and reason for use. After the initial medication reconciliation the investigators will review the participant's medications with pharmacy to determine if any significant drug-drug interactions exist between the participant's medications and D-Cycloserine. If such interactions are discovered the investigators will collaborate with the participant's prescribing physician to determine if dose alterations/discontinuation would benefit the participant while receiving D-Cycloserine therapy. For subsequent medication reconciliations at follow up visits the investigators will do the same for any new medications that the participant may be taking.

After clinical assessments, the investigators will routinely return results to the participant by phone or by secure messaging in the EMR (per standard clinical protocol).

In addition to the scheduled study visits the participant is encouraged to follow up with the the investigators via phone or by secure messaging in the EMR should they have any questions or updates about interval changes in the participant's clinical status. Each report will be assessed by the investigators and based on their clinical judgement the participant may require additional follow up evaluations.

If the results are acceptable and there is no contraindication to treatment the investigators will begin dosing D-Cycloserine following the baseline visit.

The D-Cycloserine (250 mg) capsules will be compounded to a suspension of 25 mg/mL, and for a starting dose the participant would take 15 mg/kg (253 mg = 10.1 mL) by mouth once daily. Throughout the study, based on serial clinical evaluations, sphingolipid levels, and toxicity monitoring the investigators will adjust the dose between 15-20 mg/kg/day at the discretion of the Principle Investigator (PI). The PI reserves the right to stop, temporarily hold, or adjust the dose of the medication at their discretion. As the participant grows and gains weight the investigators will adjust the dose as necessary in order to keep it at the goal of 15 to 20 mg/kg/day.

The time to peak concentration for D-cycloserine is 4 to 8 hours with a half-life elimination (with normal renal function) of 12 hours. Studies in pediatric patients recommend targeting serum concentrations of 25 to 30 mcg/mL to minimize neurotoxicity. Therefore ~6 hours after initial administration the investigators would draw a D-Cycloserine level to best understand the peak concentration obtained in the participant.

Given that concomitant pyridoxine is recommended to prevent cycloserine-induced neuropathy, at the time of D-Cycloserine initiation the investigators would also plan to supplement with pyridoxine. The pyridoxine (50 mg) tablets will be compounded to a suspension of 50 mg/mL, and the participant will take 0.4 mL (20 mg = approximately 1.18 mg/kg) by mouth once daily. If there is ongoing concern for drug related neuropathy at this starting dose then pyridoxine dose adjustments can be made towards a max of 2 mg/kg/day.

The schedule of assessments will be followed as long as the participant tolerates the treatment and continues to do well clinically. If there are concerns for tolerability, adverse events, or serious adverse events, at their discretion the PI reserves the right to stop, temporarily hold, or adjust the dose of the medication as well as increase the frequency of follow up assessments.

Weekly assessments will be conducted by the investigators to assess outcomes measures for the four weeks following the baseline visit. Following this period, outcome measures will be assessed every two weeks for a period of 8 weeks. Afterwards, pending reassuring data and lack of contraindications the investigators will space out assessments to once a month. At the 6 month interval assessment, a repeat MRI and Lumbar Puncture will be performed. Visits will continue monthly until 1 year post-baseline. A final MRI and Lumbar Puncture will be performed at the 1 year interval visit.

Inclusion criteria

• • Informed consent provided by the participant's parents.

• Ability to travel to the study and assessment sites (Massachusetts General Hospital Main Campus, 55 Fruit St, Boston, MA 02114 and MGH IHP Impact Practice Center, 2 Constitution Wharf, Charlestown, MA 02129) and adhere to study-related follow-up examinations and/or procedures and provide access to participant's medical records.
• Clinical phenotype, neuroimaging, genetic testing and biochemical results consistent with a diagnosis of SPTSSA-related Complex Hereditary Spastic Paraplegia

Exclusion criteria

• • Participant has any known contraindication to or unwillingness to undergo procedures listed in the protocol

• Use of investigational medication within 5 half-lives of the drug at enrollment
• Participant has any condition that, in the opinion of the Site Investigator, would ultimately prevent the completion of study procedures.