Table 1 Characteristics of included studies

Swedish Cohort studies

Fahnehjelm 2008 [21]

Cohort study

Average follow-up time: median 7.5 years (range 2.3–14.8 years)

Study period: Not reported

Study setting: Karolinska University Hospital and Uppsala University Hospital, Sweden

Number of centres: 2

n = 10, 10/10 LCHADD.

Asymptomatic screened: n = 1 (cascade testing).

Age of diagnosis/treatment: First days of life

Clinical presentation with symptoms: n = 9

Clinical symptoms (S) but no acute illness: n = 4

Severe symptoms (SS) (elevated liver enzymes and cardiomyopathy and /or seizures): n = 5

Age of diagnosis/treatment:

0-1 m (n = 1), 1-6 m (n = 2), > 6 m (n = 6)

All patients received a dietary treatment of low fat intake and essential fatty acid supplementation. All children also received DHA.

Compliance of treatment is not reported.

Fahnehjelm 2016 [22]

Cohort study. Prospective and retrospective data collection

Average follow up time: median 15 years (range 3–26 years).

Time period/study duration: Not reported

Patients diagnosed between 1990 to using the same treatment guidelines

Study setting: Karolinska University Hospital and Uppsala University Hospital, Sweden

Number of centres: 2

n = 12, 12/12 LCHADD.

Asymptomatic screened n = 3 (2 by NBS, 1 unspecified).

Age of diagnosis/treatment: First days of life

Clinical presentation with symptoms: n = 9

Clinical symptoms (S) but no acute illness: n = 4

Severe symptoms (SS) (elevated liver enzymes and cardiomyopathy and /or seizures): n = 5

Age of diagnosis/treatment:

0-1 m (n = 1), 1-6 m (n = 2), > 6 m (n = 6)

All patients received a dietary treatment of low fat intake and essential fatty acid supplementation.

11/12 had DHA.

8/12 continuous night feeds.

Dietary compliance:

Asymptomatic screened: all acceptable

S clinical:

1/4 (25%) poor, 3/4 (75%) acceptable

SS clinical:

3/5 (60%) poor, 2/5 (40%) acceptable

Haglind 2013 [23]

Cohort study, retrospective data collection of medical reviews

Time period/study duration: Not reported

Patients aged up to 20 years

Study setting: Karolinska University Hospital and Uppsala University Hospital, Sweden

Number of centres: 2

n = 10, 10/10 LCHADD.

Asymptomatic screened: n = 1 (cascade testing).

Age of diagnosis/treatment: 2 days

Clinical presentation with symptoms: n = 9

Clinical symptoms (S) but no acute illness: n = 4

Severe symptoms (SS) (elevated liver enzymes and cardiomyopathy and / or seizures): n = 5

Age of diagnosis/treatment:

mean 6.1 months (up to 13 m)

8/10 received DHA.

9/10 had a PEG with continuous night feeds.

9/10 received MCT fat, vitamins, minerals, and trace elements.

Fasting limited to 3–4 h.

2/10 uncooked corn starch.

1 had carnitine deficiency so given carnitine supplements of 25-50 mg/kg/day.

Did not record compliance.

Prospective cohort (followed prospectively but using diagnosis data from retrospectively collected hospital records). Comparison with historical cohort (24/28 diagnosed post mortem)

Follow-up time (age of patients at the end of the study): 1–11 years

Time period: 1997–2010

Study setting: Hospitals in Finland

Number of centres: NR

n = 16, 16/16 LCHADD.

Asymptomatic screened: n = 1 (cascade testing)

Age at treatment: Birth

Symptomatic clinical: n = 15

Age at presentation:

Birth to 0.42 years (~ 5 months). Mean 0.27 years.

Age at diagnosis:

Up to 6 months

Age at treatment initiation: 1–30 days of diagnosis

All patients in both groups received a low-fat diet, MCT, essential fatty acids and DHA (this was 10 clinical patients as the remainder were not alive).

Fasting of more than 3 or 4 h avoided in infancy and childhood.

Good compliance of diet in 9/11 patients.

Case series (6 cases) – clinical histories obtained from referring physicians

Maximum follow up until age 5 years

Study duration: 3 years

Study setting: University Children’s hospital, Düsseldorf, Germany

Number of centres: 1

n = 6, 3/6 LCHADD, 3/6 MTPD.

Asymptomatic screened: n = 3 (1 LCHADD, 2 MPTD)

All diagnosed and began treatment 4–5 days of age

Symptomatic screened: n = 3 (2 LCHADD, 1 MTPD)

Type of treatment not reported.

Dietary adherence not reported.

Retrospective cohort (review of medical records)

Study duration: Birth – October 2013

Follow-up time:

Range 0.9–15.4 years (median 7.8 years,

mean 6.9 years)

Study setting:

Metabolic Centres in Austria (Graz, Innsbruck, Salzburg, Vienna) and Germany (Munich)

Number of centres: 5

n = 14, 14/14 LCHADD.

Asymptomatic screened: n = 6

Age at diagnosis median (range): 1.5 days (1–10 days)

Symptomatic screened: n = 3

Age at diagnosis median (range): 15 days (15 days)

Pre-NBS clinical: n = 3

Age at diagnosis median (range): 5 months (3–20 months)

False negative (FN) screen clinical: n = 2

Age at diagnosis median (range): 4.5 months (4–5 months)

All cases received low-fat diet and MCT supplements.

Triheptanoin was used in 2/3 symptomatic screened, 1/3 pre- NBS and 1/2 FN NBS.

Essential fatty acids (walnut oil) were given to 2/3 pre-NBS clinical cases.

DHA given to 6/6 asymptomatic screened, 1/3 symptomatic screened, 2/3 pre-NBS and 1/2 in FN NBS.

PEG used in 1/6 asymptomatic screened, 1/3 pre-NBS and 1/2 FN NBS

Dietary compliance not reported.

Retrospective cohort (questionnaire study)

Follow-up time: NR

Study setting:

Metabolic Centres, Germany/Switzerland/

Austria/the Netherlands

Number of centres: 18

n = 75, Relevant to this review: n = 27,

20/27 LCHADD, 7/27 MTPD.

Screened: n = 10 (7 LCHADD, 3 MTPD).

Age at diagnosis: Newborn, 7/10 symptomatic at NBS.

Clinically diagnosed: n = 17 (13 LCHADD, 4 MTPD).

Age at diagnosis:

LCHADD: Median 5 months (range 3 days – 11 years)

MTPD: median 1 year (range 1 day - 4.5 years)

Data available on LCT and MCT in 14/27 and 17/27 of patients:

13/14 LCT intake restricted,

17/17 supplemented with MCT,

11/14 received additional carbohydrates,

2/14 on continuous overnight nasogastric tube feeding,

1 supplemented with DHA,

1 receiving Triheptanoin.

Dietary compliance not reported.

Retrospective case series (cohort)

Time period: 20/9/1994–18/8/2015

Follow up period:

Median 5.6 years (range 0.3–20.2 years)

Study setting: Oregon Health and Science University (OHSU) Casey Eye Institute, USA

Number of centres: 1

n = 21, 18/21 LCHADD, 3/21 MTPD.

Screened: n = 7 (6 LCHADD, 1 MTPD).

Age at diagnosis: newborn, 1 LCHADD case symptomatic at screening.

Clinical: n = 14 (12 LCHADD, 2 MTPD).

Age at diagnosis: median 4.5 months (range 1 day – 3 years)

A diet low in long-chain fatty acids and supplementation with MCT. All subjects and/or guardians were counselled to avoid fasting. Some subjects were prescribed oral carnitine supplements.

Dietary intake assessed by 24 h recall.

Retrospective cohort

(chart review)

Average follow-up time: nearly 10 years (mean 9.2 years, SD 5.9 years)

Study setting:

Metabolic Clinic University of Utah, USA

Number of centres: 1

n = 5, 4/5 LCHADD, 1/5 MTPD.

Asymptomatic screened: n = 1 (1 LCHADD)

Age at diagnosis: birth (NBS)

Symptomatic screened: n = 2 (1 LCHADD, 1 MTPD).

Age at diagnosis: birth (NBS)

Symptomatic clinical: n = 2 (2 LCHADD)

Age at diagnosis: Median 5 months (range 4–6 months)

All patients received low-fat diet, MCT, essential fatty acids and carnitine. All patients bar symptomatic clinical treated received cornstarch.

Both screened symptomatic cases and 1/2 clinical symptomatic patients received DHA.

One late treated patient is noted to have followed dietary therapy with variable compliance.

Double blind parallel RCT

(retrospective data collected on time of diagnosis)

Follow-up time NR

Study setting:

Oregon Health and Science University and University of Pittsburgh, USA

Number of centres: 2

n = 24

Included for this review: n = 12. 8/12 LCHADD, 4/12 MTPD.

Asymptomatic screened: n = 7 (5 LCHADD, 2 MTPD).

Age at diagnosis/treatment (range): newborn (0-2 m).

Symptomatic clinical: n = 5 (3 LCHADD, 2 MTPD).

Age at diagnosis/treatment (range):

Infancy (2 m-2y) n = 4 or childhood (2y-10y) n = 1.

All patients in the asymptomatic and symptomatic groups received a low-fat diet and MCT.

3/7 from the asymptomatic group received Triheptanoin (2 LCHADD, 1 MTP).

4/7 from the asymptomatic group received Trioctanoin (3 LCHADD, 1 MTP).

4/5 from the symptomatic group received Triheptanoin (2 LCHADD, 2 MTP)

1/5 from the symptomatic group received Trioctanoin (1 LCHADD)

Dietary compliance not reported.

Retrospective cohort

Follow-up time: ~ 10 years

Time period:

May 2002 – February 2016

Study setting:

Department of Medical Genetics, Asan Medical Center Children’s Hospital, Seoul, Korea

Number of centres: NR

n = 22

Included for this review: n = 7

LCHADD/MTPD not differentiated but genotypes are suggestive of MTPD.

Asymptomatic screened: n = 1

Symptomatic clinical: n = 6

Screened patient educated to avoid prolonged fasting, MCT diet with long-chain fat restriction

Dietary compliance not reported.

Case-control study

Follow-up time: Range 2–109 months

Time period:

Feb 1st 2002 – Mar 31st 2011 (trial 2002–2009)

Study setting:

Statens Serum Institut, Copenhagen. Cases from Denmark, Faroe Islands and Greenland

Number of centres: 1

n = 5

LCHADD and MTPD not differentiated.

Asymptomatic screened: n = 3

Age at diagnosis/treatment median (range): 6 days (1d-5d)

Symptomatic clinical: n = 2

Age at diagnosis/treatment median (range): 4.5 months (4.5 months)

Type of dietary management not reported

Dietary compliance not reported.

Retrospective cohort

Follow-up time: Up to 17 years

Time period: 1992–2009

Study setting: Children’s Memorial Health Institute and Institute of Mother and Child Warsaw, Poland

Number of centres: 2

n = 59, 58/58 LCHADD, 1 not analysed.

Asymptomatic screened: n = 15

Age at diagnosis/treatment:

Median 14 days (range 4 days - 8 weeks)

Detected by cascade testing, TMS pilot screening or by chance from PKU screening.

Symptomatic clinical: n = 44

Age at diagnosis/treatment: median (range): 6 m (1 m-18y1m) Group includes all those tested due to suspicions of metabolic disorders post mortem and diagnoses established abroad.

Type of dietary management not reported.

Dietary compliance not reported.