A Natural History of Late Onset Tay-Sachs Disease

For this study, subjects will come to Massachusetts General Hospital for two study visits,
six months apart. At each visit, the following tests will be done:

A Neurological Exam, Several Ataxia Rating Scales, A Formal Speech assessment, Magnetic
resonance imaging and spectroscopy, A blood draw, An optional lumbar puncture.

Outcome measures and biomarkers (MRI atrophy measures, chemical shift imaging (CSI), MRS and
CSF metabolites) will be compared to the clinical disease course in Late Onset GM2
Gangliosidosis. The natural history by retrospective surveys (previously acquired) will shed
light on how changes in outcome measures compare to the larger context of changing symptoms
(that occurs on the scale of years and decades). This combined approach will elucidate
optimal outcome measures and determine eligibility criteria for a future clinical trial in
Late Onset GM2 Gangliosidosis.

The international web-based platform for clinical research networks, NeuroBANK™, in which
clinicians and researchers collect and share their patients' clinical and research data, will
be used. This system has been implemented by and deployed at the Neurological Clinical
Research Institute at Massachusetts General Hospital. This platform allows clinicians to
enter patient data, either a) manually via a Web-based interface, or b) by exporting the data
from the electronic health record (EHR) and clinical data repositories.

GLOBAL UNIQUE IDENTIFIERS (GUID):

A patient Global Unique Identifier (GUID) will be used as the identifier for individuals
participating in the study in NeuroBANK™. The GUID is an 11-character string that is
generated using encryption technology and algorithms licensed by the NCRI from the National
Institutes of Health (NIH).

The GUID is generated on a secure website that utilizes 128-bit Secure Socket Layer (SSL). Of
note, this website is not linked to NeuroBANK™. The GUID is generated using an irreversible
encryption algorithm - it accepts twelve identifying data elements, (e.g. last name at birth,
first name at birth, gender at birth, day, month and year of birth, city and country of
birth, etc.), and produces a unique random-generated character string, or GUID. No
identifying information is stored in the system; it is simply used to generate the GUID. If
the same information is entered again, the same GUID will be returned.

The GUID is entered into NeuroBANK™ when the patient is being created in the system. As the
same patient may participate in multiple studies, NeuroBANK™ will also allow capturing a
study-specific ID for the patient. For more information about NeuroBANK™ or the GUID, please
go to: www.neurobank.org.

Data Management:

The NCRI Data Management Team is trained and knowledgeable regarding confidentiality and
integrity of data. They will be responsible for all aspects of data procedures. Alex Sherman
is the ALD Connect network strategist and member of the NEALS ALS consortium. He is the
director of Strategic Development and Systems of NCRI, serves on the Executive Committee of
the ALS Research Group, and is one of the leaders of the NEALS ALS Consortium.

Data Quality Checks, Logic Checks and Queries:

The Data Manager (DM) at the Neurological Clinical Research Institute (NCRI) at the
Massachusetts General Hospital will conduct monthly Data Quality Checks, Logic Checks, and
internal data quality audits. Data field queries will be resolved in an established workflow
according to the Standard Operating Procedures (SOPs). The queries may be created either at
the point of entry during the data entry process, manually by the NCRI DM, or as the result
of executing monthly Logic Checks.

Study-Specific Database Backup and Maintenance:

The NCRI personnel will be responsible for the database backups that will be conducted daily.
Simultaneously, a separate copy of the backup in the encrypted compressed format will be
maintained and saved by the System Analysts. The backups will be saved on a separate computer
partition in a password-protected compressed format and also will be burnt into DVD medium
and stored in a secure location.

Inclusion Criteria:

- The subject must have a confirmed diagnosis of Late Onset GM2 Gangliosidosis as
defined by (a) absent to near-absent beta-hexosaminidase enzymatic activity in the
serum or white blood cells or (b) mutation analysis of the HEXA and HEXB genes to
distinguish pseudo deficiency alleles from disease-causing alleles

- The subject must be older than 7 years of age

Exclusion Criteria:

- If a patient is very severely affected by the disease, the PI will assess whether it
is in the best interest of the patient to exclude them from the study for their own
comfort and well being. In cases where the PI deems it appropriate, severely affected
patients will be excluded. Patients under the age of 7 years will be excluded from
this study.